Imidazo[4,5-c]quinolin-2-one Compounds and Their Use in Treating Cancer

ABSTRACT

The specification generally relates to compounds of Formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts thereof, where R 1 , R 2 , R 3 , R 4  and R 5  have any of the meanings defined herein. The specification also relates to the use of compounds of Formula (I) and salts thereof to treat or prevent ATM mediated disease, including cancer. The specification further relates to pharmaceutical compositions comprising to substituted imidazo[4,5-c]quinolin-2-one compounds and pharmaceutically acceptable salts thereof; kits comprising such compounds and salts; methods of manufacture of such compounds and salts; and intermediates useful in such manufacture.

FIELD OF INVENTION

In accordance with 35 U.S.C. 119(a)-(d) and (f), 172, 365(a) and (b),386(a) and (b), and 37 CFR 1.55 this application claims the benefit ofGB Application No. 1516504.6 filed on 17 Sep. 2015.

This specification relates to substituted imidazo[4,5-c]quinolin-2-onecompounds and pharmaceutically acceptable salts thereof. These compoundsand salts selectively to modulate ataxia telangiectasia mutated (“ATM”)kinase, and the specification therefore also relates to the use ofsubstituted imidazo[4,5-c]quinolin-2-one compounds and salts thereof totreat or prevent ATM mediated disease, including cancer. Thespecification further relates to pharmaceutical compositions comprisingsubstituted imidazo[4,5-c]quinolin-2-one compounds and pharmaceuticallyacceptable salts thereof; kits comprising such compounds and salts;methods of manufacture of such compounds and salts; and intermediatesuseful in such manufacture.

BACKGROUND

ATM kinase is a serine threonine kinase originally identified as theproduct of the gene mutated in ataxia telangiectasia. Ataxiatelangiectasia is located on human chromosome 11q22-23 and codes for alarge protein of about 350 kDa, which is characterized by the presenceof a phosphatidylinositol (“PI”) 3-kinase-like serine/threonine kinasedomain flanked by FRAP-ATM-TRRAP and FATC domains which modulate ATMkinase activity and function. ATM kinase has been identified as a majorplayer of the DNA damage response elicited by double strand breaks. Itprimarily functions in S/G2/M cell cycle transitions and at collapsedreplication forks to initiate cell cycle checkpoints, chromatinmodification, HR repair and pro-survival signalling cascades in order tomaintain cell integrity after DNA damage (Lavin, M. F.; Rev. Mol. CellBiol. 2008, 759-769).

ATM kinase signalling can be broadly divided into two categories: acanonical pathway, which signals together with the Mre11-Rad50-NBS1complex from double strand breaks and activates the DNA damagecheckpoint, and several non-canonical modes of activation, which areactivated by other forms of cellular stress (Cremona et al., Oncogene2013, 3351-3360).

ATM kinase is rapidly and robustly activated in response to doublestrand breaks and is reportedly able to phosphorylate in excess of 800substrates (Matsuoka et al., Science 2007, 1160-1166), coordinatingmultiple stress response pathways (Kurz and Lees Miller, DNA Repair2004, 889-900). ATM kinase is present predominantly in the nucleus ofthe cell in an inactive homodimeric form but autophosphorylates itselfon Ser1981 upon sensing a DNA double strand break (canonical pathway),leading to dissociation to a to monomer with full kinase activity(Bakkenist et al., Nature 2003, 499-506). This is a critical activationevent, and ATM phospho-Ser1981 is therefore both a directpharmacodynamic and patient selection biomarker for tumour pathwaydependency.

ATM kinase responds to direct double strand breaks caused by commonanti-cancer treatments such as ionising radiation and topoisomerase-IIinhibitors (doxorubicin, etoposide) but also to topoisomerase-Iinhibitors (for example irinotecan and topotecan) via single strandbreak to double strand break conversion during replication. ATM kinaseinhibition can potentiate the activity of any these agents, and as aresult ATM kinase inhibitors are expected to be of use in the treatmentof cancer.

CN102372711A reports certain imidazo[4,5-c]quinolin-2-one compoundswhich are mentioned to be dual inhibitors of PI 3-kinase α and mammaliantarget of rapamycin (“mTOR”) kinase. Among the compounds reported inCN102372711A are the following:

CN102399218A reports certain imidazo[4,5-c]quinolin-2-one compoundswhich are mentioned to be PI 3-kinase α inhibitors. Among the compoundsreported in CN102399218A are the following:

While the compounds or CN102372711A and CN102399218A are reported topossess activity against PI 3-kinase α and in some cases mTOR kinase,there remains a need to develop new compounds that are more effectiveagainst different kinase enzymes, such as ATM kinase. There furtherexists a need for new compounds which act against certain kinaseenzymes, like ATM kinase, in a highly selective fashion (i.e. bymodulating ATM more effectively than other biological targets).

As demonstrated elsewhere in the specification (for example in the cellbased assays described in the experimental section), the compounds ofthe present specification generally possess very potent ATM kinaseinhibitory activity, but much less potent activity against othertyrosine kinase enzymes, such as PI 3-kinase α, mTOR kinase and ataxiatelangiectasia and Rad3-related protein (“ATR”) kinase. As such, thecompounds of the present specification not only inhibit ATM kinase, butcan be considered to be highly selective inhibitors of ATM kinase.

As a result of their highly selective nature, the compounds of thepresent specification are expected to be particularly useful in thetreatment of diseases in which ATM kinase is implicated (for example, inthe treatment of cancer), but where it is desirable to minimiseoff-target effects or toxicity that might arise due to the inhibition ofother tyrosine kinase enzymes, such as class PI 3-kinase α, mTOR kinaseand ATR kinase.

SUMMARY OF INVENTION

Briefly, this specification describes, in part, a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, where:

R¹ is methyl;

R² is hydro or methyl; or R¹ and R² together with the nitrogen atom towhich they are bonded form an azetidinyl, pyrrolidinyl or piperidinylring;

R³ is hydro or fluoro;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro.

This specification also describes, in part, a pharmaceutical compositionwhich comprises a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in therapy.

This specification also describes, in part, a compound of Formula (I),or a pharmaceutically acceptable salt thereof, for use in the treatmentof cancer.

This specification also describes, in part, the use of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of cancer.

This specification also describes, in part, a method for treating cancerin a warm blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof.

FIGURES

FIG. 1: X-Ray Powder Diffraction Pattern of Form A of7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

FIG. 2: DSC Thermogram of Form A of7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

FIG. 3: X-Ray Powder Diffraction Pattern of Form B of7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

FIG. 4: DSC Thermogram of Form B of7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Many embodiments of the invention are detailed throughout thespecification and will be apparent to a reader skilled in the art. Theinvention is not to be interpreted as being limited to any particularembodiment(s) thereof.

In the first embodiment there is provided a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, where:

R¹ is methyl;

R² is hydro or methyl; or R¹ and R² together with the nitrogen atom towhich they are bonded form an azetidinyl, pyrrolidinyl or piperidinylring;

R³ is hydro or fluoro;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro.

A “hydro” group is equivalent to a hydrogen atom. Atoms with a hydrogroup attached to them can be regarded as unsubstituted.

Where it is mentioned that “R¹ and R² together with the nitrogen atom towhich they are bonded form an azetidinyl, pyrrolidinyl or piperidinylring”, this means the R¹ and R² groups are joined via a carbon-carboncovalent bond to form an unsubstituted alkylene chain of the appropriatelength to form the corresponding ring. For example, when R¹ and R²together with the nitrogen atom to which they are bonded form apyrrolidinyl ring, R¹ and R² together represent an unsubstitutedbutylene chain which is attached to the relevant nitrogen atom inFormula (I) at both terminal carbons.

The term “pharmaceutically acceptable” is used to specify that an object(for example a salt, dosage form or excipient) is suitable for use inpatients. An example list of pharmaceutically acceptable salts can befound in the Handbook of Pharmaceutical Salts: Properties, Selection andUse, P. H. Stahl and C. G. Wermuth, editors,Weinheim/Zfirich:Wiley-VCH/VHCA, 2002. A suitable pharmaceuticallyacceptable salt of a compound of Formula (I) is, for example, anacid-addition salt. An acid addition salt of a compound of Formula (I)may be formed by bringing the compound into contact with a suitableinorganic or organic acid under conditions known to the skilled person.An acid addition salt may for example be formed using an inorganic acidselected from the group consisting of hydrochloric acid, hydrobromicacid, sulphuric acid and phosphoric acid. An acid addition salt may alsobe formed using an organic acid selected from the group consisting oftrifluoroacetic acid, citric acid, maleic acid, oxalic acid, aceticacid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaricacid, lactic acid, pyruvic acid, methanesulfonic acid, benzenesulfonicacid and para-toluenesulfonic acid.

Therefore, in one embodiment there is provided a compound of Formula (I)or a pharmaceutically acceptable salt thereof, where thepharmaceutically acceptable salt is a hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, trifluoroacetic acid, citricacid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid,fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid,methanesulfonic acid, benzenesulfonic acid orpara-toluenesulfonic acidsalt. In one embodiment there is provided a compound of Formula (I) or apharmaceutically acceptable salt thereof, where the pharmaceuticallyacceptable salt is a methanesulfonic acid salt. In one embodiment thereis provided a compound of Formula (I) or a pharmaceutically acceptablesalt thereof, where the pharmaceutically acceptable salt is amono-methanesulfonic acid salt, i.e. the stoichiometry of the compoundof the compound of Formula (I) to methanesulfonic acid is 1:1.

A further embodiment provides any of the embodiments defined herein (forexample the embodiment of claim 1) with the proviso that one or morespecific Examples (for instance one, two or three specific Examples)selected from the group consisting of Examples 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17 and 18 is individually disclaimed.

Some values of variable groups in Formula (I) are as follows. Suchvalues may be used in combination with any of the definitions, claims(for example claim 1), or embodiments defined herein to provide furtherembodiments.

-   -   a) R¹ is methyl.    -   b) R² is methyl.    -   c) R² is hydro.    -   d) R¹ is methyl and R² is hydro or methyl.    -   e) R¹ and R² are both methyl.    -   f) R¹ and R² are both methyl; or R¹ and R² together with the        nitrogen atom to which they are bonded form an azetidinyl,        pyrrolidinyl or piperidinyl ring.    -   g) R¹ and R² are both methyl; or R¹ and R² together with the        nitrogen atom to which they are bonded form an azetidinyl ring.    -   h) R¹ and R² are both methyl; or R¹ and R² together with the        nitrogen atom to which they are bonded form a pyrrolidinyl ring.    -   i) R¹ and R² are both methyl; or R¹ and R² together with the        nitrogen atom to which they are bonded form a piperidinyl ring.    -   j) R¹ and R² are both methyl.    -   k) R¹ and R² together with the nitrogen atom to which they are        bonded form an azetidinyl, pyrrolidinyl or piperidinyl ring.    -   l) R¹ and R² together with the nitrogen atom to which they are        bonded form an azetidinyl ring.    -   m) R¹ and R² together with the nitrogen atom to which they are        bonded form a pyrrolidinyl ring.    -   n) R¹ and R² together with the nitrogen atom to which they are        bonded form a piperidinyl ring.    -   o) R³ and R⁵ are both hydro.    -   p) R³ and R⁵ are both fluoro.    -   q) R³ is hydro.    -   r) R³ is fluoro.    -   s) R⁴ is hydro.    -   t) R⁴ is methyl.    -   u) R⁵ is hydro.    -   v) R⁵ is fluoro.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, where:

R¹ is methyl;

R² is hydro or methyl; or R¹ and R² together with the nitrogen atom towhich they are bonded form an azetidinyl, pyrrolidinyl or piperidinylring;

R³ is hydro or fluoro;

R⁴ is hydro or methyl; and

R⁵ is hydro or fluoro.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, where:

R¹ is methyl;

R² is hydro or methyl;

R³ is hydro;

R⁴ is hydro or methyl; and

R⁵ is hydro.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, where the compound is selectedfrom the group consisting of:

-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   7-Fluoro-1-isopropyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(azetidin-1-yl)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   1-Isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   1-isopropyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Azetidin-1-yl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[2-Fluoro-6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(dimethylamino)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[2-fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   7-fluoro-8-[2-fluoro-6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   7-fluoro-8-[2-fluoro-6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(azetidin-1-yl)propoxy]-2-fluoro-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(azetidin-1-yl)propoxy]-2-fluoro-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one;-   8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one;    and-   7-Fluoro-1-isopropyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]-3H-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a pharmaceutically acceptable saltof7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided8-[6-[3-(azetidin-1-yl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided8-[6-[3-(azetidin-1-yl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a pharmaceutically acceptable saltof8-[6-[3-(azetidin-1-yl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a pharmaceutically acceptable saltof8-[6-[3-(dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-oxidopiperidin-1-ium-1-yl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.

In one embodiment there is provided7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-oxidopiperidin-1-ium-1-yl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a pharmaceutically acceptable saltof7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-oxidopiperidin-1-ium-1-yl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

Compounds and salts described in this specification may exist insolvated forms and unsolvated forms. For example, a solvated form may bea hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, atri-hydrate or an alternative quantity thereof.

The invention encompasses all such solvated and unsolvated forms ofcompounds of Formula (I), particularly to the extent that such formspossess ATM kinase inhibitory activity, as for example measured usingthe tests described herein.

Atoms of the compounds and salts described in this specification mayexist as their isotopes. The invention encompasses all compounds ofFormula (I) where an atom is replaced by one or more of its isotopes(for example a compound of Formula (I) where one or more carbon atom isan ¹¹C or ¹³C carbon isotope, or where one or more hydrogen atoms is a²H or ³H isotope).

Compounds and salts described in this specification may exist as amixture of tautomers. “Tautomers” are structural isomers that exist inequilibrium resulting from the migration of a hydrogen atom. Theinvention includes all tautomers of compounds of Formula (I)particularly to the extent that such tautomers possess ATM kinaseinhibitory activity.

Compounds and salts described in this specification may be crystalline,and may exhibit one or more crystalline forms. The invention encompassesany crystalline or amorphous form of a compound of Formula (I), ormixture of such forms, which possesses ATM kinase inhibitory activity.

It is generally known that crystalline materials may be characterisedusing conventional techniques such as X-Ray Powder Diffraction (XRPD),Differential Scanning Calorimetry (DSC), Thermal Gravimetric Analysis(TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT)spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solidstate nuclear magnetic resonance spectroscopy. The water content ofcrystalline materials may be determined by Karl Fischer analysis.

The crystalline forms described herein provide XRPD patternssubstantially the same as the XRPD patterns shown in the Figures, andhave the various 2-theta values as shown in the Tables included herein.One skilled in the art will understand that an XRPD pattern ordiffractogram may be obtained which has one or more measurement errorsdepending on the recording conditions, such as the equipment or machineused. Similarly, it is generally known that intensities in an XRPDpattern may fluctuate depending on measurement conditions or samplepreparation as a result of preferred orientation. Persons skilled in theart of XRPD will further realise that the relative intensity of peakscan also be affected by, for example, grains above 30 μm in size andnon-unitary aspect ratios. The skilled person understands that theposition of reflections can be affected by the precise height at whichthe sample sits in the diffractometer, and also the zero calibration ofthe diffractometer. The surface planarity of the sample may also have asmall effect.

As a result of these considerations, the diffraction pattern datapresented are not to be taken as absolute values (Jenkins, R & Snyder,R. L. ‘Introduction to X-Ray Powder Diffractometry’ John Wiley & Sons1996; Bunn, C. W. (1948), ‘Chemical Crystallography’, Clarendon Press,London; Klug, H. P. & Alexander, L. E. (1974), ‘X-Ray DiffractionProcedures’). It should correspondingly be understood that the solidforms are not limited to the crystals that provide XRPD patterns thatare identical to the XRPD pattern shown in the Figures, and any crystalsproviding XRPD patterns substantially the same as those shown in theFigures fall within the scope of the invention. A person skilled in theart of XRPD is able to judge the substantial identity of XRPD patterns.Generally, a measurement error of a diffraction angle in an XRPD isapproximately plus or minus 0.2° 2-theta, and such degree of ameasurement error should be taken into account when considering theX-ray powder diffraction pattern in the Figures and when reading datacontained in the Tables included herein.

The compound of Example 2 exhibits crystalline properties, and onecrystalline form has been characterised.

Therefore, in one embodiment there is provided Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at about 2-theta=22.7°.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at about 2-theta=23.4°.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at about 2-theta=22.7 and 23.4°.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at about 2-theta=3.7 and 14.8°.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with specific peaks atabout 2-theta=3.7, 11.3, 13.1, 14.8, 18.0, 18.4, 19.4, 21.0, 22.3 and23.2°.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has an X-ray powder diffraction pattern substantially the same asthe X-ray powder diffraction pattern shown in FIG. 1.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=22.7° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=23.4° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at 2-theta=22.7 and 23.4° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=3.7° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=14.8° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at 2-theta=3.7 and 14.8° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with specific peaks at2-theta=3.7, 11.3, 13.1, 14.8, 18.0, 18.4, 19.4, 21.0, 22.3 and 23.2°plus or minus 0.2° 2-theta.

DSC analysis of Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-oneshows a melting endotherm with an onset of 141.5° C. and a peak at144.2° C. (FIG. 2).

A person skilled in the art understands that the value or range ofvalues observed in a particular compound's DSC Thermogram will showvariation between batches of different purities. Therefore, whilst forone compound the range may be small, for others the range may be quitelarge. Generally, a measurement error of a diffraction angle in DSCthermal events is approximately plus or minus 5° C., and such degree ofa measurement error should be taken into account when considering theDSC data included herein.

Therefore, in one embodiment there is provided a crystalline form, FormA of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at about 141.5° C.and a peak at about 144.2° C.

Therefore, in one embodiment there is provided a crystalline form, FormA of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at 141.5° C. plus orto minus 5° C. and a peak at 144.2° C. plus or minus 5° C.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at 141.5° C. and apeak at 144.2° C.

In one embodiment there is provided a crystalline form, Form A of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC thermogram substantially as shown in FIG. 2.

In one embodiment there is provided Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at about 2-theta=14.8°.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at about 2-theta=21.0°.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at about 2-theta=14.8 and 21.0°.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at about 2-theta=3.4 and 11.7°.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with specific peaks atabout 2-theta=3.4, 11.7, 13.1, 13.5, 17.5, 18.1, 19.0, 22.7, 23.4 and24.0⁰.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has an X-ray powder diffraction pattern substantially the same asthe X-ray powder to diffraction pattern shown in FIG. 3.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=14.8° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=21.0° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at 2-theta=14.8 and 21.0° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=3.4° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least one specificpeak at 2-theta=11.7° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with at least two specificpeaks at 2-theta=3.4 and 11.7° plus or minus 0.2° 2-theta.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,which has an X-ray powder diffraction pattern with specific peaks at2-theta=3.4, 11.7, 13.1, 13.5, 17.5, 18.1, 19.0, 22.7, 23.4 and 24.0°plus or minus 0.2° 2-theta.

DSC analysis of Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-oneshows a melting endotherm with an onset of 144.7° C. and a peak at145.8° C. (FIG. 4).

Therefore, in one embodiment there is provided a crystalline form, FormB of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at about 144.7° C.and a peak at about 145.8° C.

Therefore, in one embodiment there is provided a crystalline form, FormB of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at 144.7° C. plus orminus 5° C. and a peak at 145.8° C. plus or minus 5° C.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC endotherm with an onset of melting at 144.7° C. and apeak at 145.8° C.

In one embodiment there is provided a crystalline form, Form B of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onewhich has a DSC thermogram substantially as shown in FIG. 4.

When it is stated that an embodiment relates to a crystalline form, thedegree of crystallinity may be greater than about 60%. In someembodiments the degree of crystallinity is greater than about 80%. Insome embodiments the degree of crystallinity is greater than about 90%.In some embodiments the degree of crystallinity is greater than about95%. In some embodiments the degree of crystallinity is greater thanabout 98%. Compounds of Formula (I) may for example be prepared by thereaction of a compound of Formula (II):

or a salt thereof, where R³, R⁴ and R⁵ are as defined in any of theembodiments herein and X is a leaving group (for example a halogen atom,or alternatively a fluorine atom) with a compound of formula (III):

or a salt thereof, where R¹ and R² are as defined in any of theembodiments herein. The reaction is conveniently performed in a suitablesolvent (for example DMF, DMA or THF) and in the presence of a base (forexample sodium hydride) at a suitable temperature (for example atemperature in the range of about 20-50° C.).

Compounds of Formula (II), and salts thereof, are therefore useful asintermediates in the preparation of the compounds of Formula (I) andprovide a further embodiment. In one embodiment there is provided acompound of Formula (II), or a salt thereof, where:

R³ is hydro or fluoro;

R⁴ is hydro or methyl;

R⁵ is hydro or fluoro; and

X is a leaving group. In one embodiment X is a halogen atom or atriflate group. In one embodiment X is a fluorine atom.

In one embodiment there is provided7-fluoro-8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one,or a salt thereof.

In one embodiment there is provided8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one,or a salt thereof.

In any of the embodiments where a compound of Formula (II) or a saltthereof is mentioned it is to be understood that such salts do not needto be pharmaceutically acceptable salts. A suitable salt of a compoundof Formula (II) is, for example, an acid-addition salt. An acid additionsalt of a compound of Formula (II) may be formed by bringing thecompound into contact with a suitable inorganic or organic acid underconditions known to the skilled person. An acid addition salt may forexample be formed using an inorganic acid selected from the groupconsisting of hydrochloric acid, hydrobromic acid, sulphuric acid andphosphoric acid. An acid addition salt may also be formed using anorganic acid selected from the group consisting of trifluoroacetic acid,citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoicacid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvicacid, methanesulfonic acid, benzenesulfonic acid andpara-toluenesulfonic acid.

Therefore, in one embodiment there is provided a compound of Formula(II) or a salt thereof, where the salt is a hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid,citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoicacid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvicacid, methanesulfonic acid, benzenesulfonic acid or para-toluenesulfonicacid salt.

The compounds of Formula (II) may for example be prepared by thereaction of a compound of Formula (IV):

where R⁴ and R⁵ are as defined in any of the embodiments herein and X¹is a leaving group (for example an iodine, bromine, or chlorine atom ora triflate group, or alternatively a bromine atom) with a compound offormula (V):

or a salt thereof, where R³ and X are as defined in any of theembodiments herein and Y is a boronic acid, boronic ester or potassiumtrifluoroborate group (for example boronic acid, boronic acid pinacolester, or potassium trifluoroborate). The reaction may be performedunder standard conditions well known to those skilled in the art, forexample in the presence of a palladium source (for example tetrakistriphenylphosphine palladium or palladium(II) acetate), optionally aphosphine ligand (for example Xantphos or S-phos), and a suitable base(for example cesium carbonate or triethylamine).

Compounds of Formula (IV) are therefore useful as intermediates in thepreparation of the compounds of Formula (I) and provide a furtherembodiment. In one embodiment there is provided a compound of Formula(IV), or a salt thereof, where:

R⁴ is hydro or methyl;

R⁵ is hydro or fluoro; and

X¹ is a leaving group. In one embodiment X¹ is an iodine, bromine, orchlorine atom or a triflate group. In one embodiment X¹ is a bromineatom.

In one embodiment there is provided8-bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one, or asalt thereof.

In one embodiment there is provided8-bromo-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one, or a saltthereof.

Compounds of formula (IV) can be prepared by methods similar to thoseshown in the Examples section.

Compounds of Formula (I) may also be prepared by the reaction of acompound of Formula (IV) as described above with a compound of formula(VI):

where R¹, R² and R³ are as defined in any of the embodiments herein andY is a boronic acid, boronic ester or potassium trifluoroborate group(for example boronic acid, boronic acid pinacol ester, or potassiumtrifluoroborate). The reaction may be performed under standardconditions well known to those skilled in the art, for example in thepresence of a palladium source (for example tetrakis triphenylphosphinepalladium or palladium(II) acetate), optionally a phosphine ligand (forexample Xantphos or S-phos), and a suitable base (for example cesiumcarbonate or triethylamine).

Compounds of formula (VI) can be prepared by methods similar to thoseshown in the Examples section.

In one embodiment there is provided any one of the novel intermediatesdescribed in the experimental section.

As a result of their ATM kinase inhibitory activity, the compounds ofFormula (I), and pharmaceutically acceptable salts thereof are expectedto be useful in therapy, for example in the treatment of diseases ormedical conditions mediated at least in part by ATM kinase, includingcancer.

Where “cancer” is mentioned, this includes both non-metastatic cancerand also metastatic cancer, such that treating cancer involves treatmentof both primary tumours and also tumour metastases.

“ATM kinase inhibitory activity” refers to a decrease in the activity ofATM kinase as a direct or indirect response to the presence of acompound of Formula (I), or pharmaceutically acceptable salt thereof,relative to the activity of ATM kinase in the absence of compound ofFormula (I), or pharmaceutically acceptable salt thereof. Such adecrease in activity may be due to the direct interaction of thecompound of Formula (I), or pharmaceutically acceptable salt thereofwith ATM kinase, or due to the interaction of the compound of Formula(I), or pharmaceutically acceptable salt thereof with one or more otherfactors that in turn affect ATM kinase activity. For example, thecompound of Formula (I), or pharmaceutically acceptable salt thereof maydecrease ATM kinase by directly binding to the ATM kinase, by causing(directly or indirectly) another factor to decrease ATM kinase activity,or by (directly or indirectly) decreasing the amount of ATM kinasepresent in the cell or organism.

The term “therapy” is intended to have its normal meaning of dealingwith a disease in order to entirely or partially relieve one, some orall of its symptoms, or to correct or compensate for the underlyingpathology. The term “therapy” also includes “prophylaxis” unless thereare specific indications to the contrary. The terms “therapeutic” and“therapeutically” should be interpreted in a corresponding manner.

The term “prophylaxis” is intended to have its normal meaning andincludes primary prophylaxis to prevent the development of the diseaseand secondary prophylaxis whereby the disease has already developed andthe patient is temporarily or permanently protected against exacerbationor worsening of the disease or the development of new symptomsassociated with the disease.

The term “treatment” is used synonymously with “therapy”. Similarly theterm “treat” can be regarded as “applying therapy” where “therapy” is asdefined herein.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in therapy.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament.

In one embodiment there is provided a compound of Formula (I), or a topharmaceutically acceptable salt thereof, for use in the treatment of adisease mediated by ATM kinase. In one embodiment, said disease mediatedby ATM kinase is cancer. In one embodiment, said cancer is selected fromthe group consisting of colorectal cancer, glioblastoma, gastric cancer,ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocyticleukaemia, acute myeloid leukaemia, head and neck squamous cellcarcinoma, breast cancer, hepatocellular carcinoma, small cell lungcancer and non-small cell lung cancer. In one embodiment, said cancer isselected from the group consisting of colorectal cancer, glioblastoma,gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chroniclymphocytic leukaemia, head and neck squamous cell carcinoma and lungcancer. In one embodiment, said cancer is colorectal cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofHuntingdon's disease.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use as a neuroprotectiveagent.

A “neuroprotective agent” is an agent that aids relative preservation ofneuronal structure and/or function.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of a disease mediated by ATM kinase.In one embodiment, said disease mediated by ATM kinase is cancer. In oneembodiment, said cancer is selected from the group consisting ofcolorectal cancer, glioblastoma, gastric cancer, ovarian cancer, diffuselarge B-cell lymphoma, chronic lymphocytic leukaemia, acute myeloidleukaemia, head and neck squamous cell carcinoma, breast cancer,hepatocellular carcinoma, small cell lung cancer and non-small cell lungcancer. In one embodiment, said cancer is selected from the groupconsisting of colorectal cancer, glioblastoma, gastric cancer, ovariancancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia,head and neck squamous cell carcinoma and lung cancer. In oneembodiment, said cancer is colorectal cancer.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of cancer.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for the treatment of Huntingdon's disease.

In one embodiment there is provided the use of the compound of Formula(I), or a pharmaceutically acceptable salt thereof, for the manufactureof a medicament for use as a neuroprotective agent.

In one embodiment there is provided a method for treating a disease inwhich inhibition of ATM kinase is beneficial in a warm-blooded animal inneed of such treatment, which comprises administering to saidwarm-blooded animal a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. In oneembodiment, said disease is cancer. In one embodiment, said cancer isselected from the group consisting of colorectal cancer, glioblastoma,gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chroniclymphocytic leukaemia, acute myeloid leukaemia, head and neck squamouscell carcinoma, breast cancer, hepatocellular carcinoma, small cell lungcancer and non-small cell lung cancer. In one embodiment, said cancer isselected from the group consisting of colorectal cancer, glioblastoma,gastric cancer, ovarian cancer, diffuse large B-cell lymphoma, chroniclymphocytic leukaemia, head and neck squamous cell carcinoma and lungcancer. In one embodiment, said cancer is colorectal cancer.

In any embodiment, a disease in which inhibition of ATM kinase isbeneficial may be Huntingdon' disease.

In one embodiment there is provided a method for effectingneuroprotection in a warm-blooded animal in need of such treatment,which comprises administering to said warm-blooded animal atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

The term “therapeutically effective amount” refers to an amount of acompound of Formula (I) as described in any of the embodiments hereinwhich is effective to provide “therapy” in a subject, or to “treat” adisease or disorder in a subject. In the case of cancer, thetherapeutically effective amount may cause any of the changes observableor measurable in a subject as described in the definition of “therapy”,“treatment” and “prophylaxis” above. For example, the effective amountcan reduce the number of cancer or tumour cells; reduce the overalltumour size; inhibit or stop tumour cell infiltration into peripheralorgans including, for example, the soft tissue and bone; inhibit andstop tumour metastasis; inhibit and stop tumour growth; relieve to someextent one or more of the symptoms associated with the cancer; reducemorbidity and mortality; improve quality of life; or a combination ofsuch effects. An effective amount may be an amount sufficient todecrease the symptoms of a disease responsive to inhibition of ATMkinase activity. For cancer therapy, efficacy in-vivo can, for example,be measured by assessing the duration of survival, time to diseaseprogression (TTP), the response rates (RR), duration of response, and/orquality of life. As recognized by those skilled in the art, effectiveamounts may vary depending on route of administration, excipient usage,and co-usage with other agents. For example, where a combination therapyis used, the amount of the compound of formula (I) or pharmaceutciallyacceptable salt described in this specification and the amount of theother pharmaceutically active agent(s) are, when combined, jointlyeffective to treat a targeted disorder in the animal patient. In thiscontext, the combined amounts are in a “therapeutically effectiveamount” if they are, when combined, sufficient to decrease the symptomsof a disease responsive to inhibition of ATM activity as describedabove. Typically, such amounts may be determined by one skilled in theart by, for example, starting with the dosage range described in thisspecification for the compound of formula (I) or pharmaceutciallyacceptable salt thereof and an approved or otherwise published dosagerange(s) of the other pharmaceutically active compound(s).

“Warm-blooded animals” include, for example, humans.

In one embodiment there is provided a method for treating cancer in awarm-blooded animal in need of such treatment, which comprisesadministering to said warm-blooded animal a therapeutically effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt thereof. In one embodiment, said cancer is selected from the groupconsisting of colorectal cancer, glioblastoma, gastric cancer, ovariancancer, diffuse large B-cell lymphoma, chronic lymphocytic leukaemia,acute myeloid leukaemia, head and neck squamous cell carcinoma, breastcancer, hepatocellular carcinoma, small cell lung cancer and non-smallcell lung cancer. In one embodiment, said cancer is selected from thegroup consisting of colorectal cancer, glioblastoma, gastric cancer,ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocyticleukaemia, head and neck squamous cell carcinoma and lung cancer. In oneembodiment, said cancer is colorectal cancer.

In any embodiment where cancer is mentioned in a general sense, saidcancer may be selected from the group consisting of colorectal cancer,glioblastoma, gastric cancer, ovarian cancer, diffuse large B-celllymphoma, chronic lymphocytic leukaemia, acute myeloid leukaemia, headand neck squamous cell carcinoma, breast cancer, hepatocellularcarcinoma, small cell lung cancer and non-small cell lung cancer. Saidcancer may also be selected from the group consisting of colorectalcancer, glioblastoma, gastric cancer, ovarian cancer, diffuse largeB-cell lymphoma, chronic lymphocytic leukaemia, head and neck squamouscell carcinoma and lung cancer.

In any embodiment where cancer is mentioned in a general sense thefollowing embodiments may apply:

In one embodiment the cancer is colorectal cancer.

In one embodiment the cancer is glioblastoma.

In one embodiment the cancer is gastric cancer.

In one embodiment the cancer is oesophageal cancer.

In one embodiment the cancer is ovarian cancer.

In one embodiment the cancer is endometrial cancer.

In one embodiment the cancer is cervical cancer.

In one embodiment the cancer is diffuse large B-cell lymphoma.

In one embodiment the cancer is chronic lymphocytic leukaemia.

In one embodiment the cancer is acute myeloid leukaemia.

In one embodiment the cancer is head and neck squamous cell carcinoma.

In one embodiment the cancer is breast cancer. In one embodiment thecancer is triple negative breast cancer.

“Triple negative breast cancer” is any breast cancer that does notexpress the genes for the oestrogen receptor, progesterone receptor andHer2/neu.

In one embodiment the cancer is hepatocellular carcinoma.

In one embodiment the cancer is lung cancer. In one embodiment the lungcancer is small cell lung cancer. In one embodiment the lung cancer isnon-small cell lung cancer.

In one embodiment the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

“Leptomeningeal metastases” occur when cancer spreads to the meninges,the layers of tissue that cover the brain and the spinal cord.Metastases can spread to the meninges through the blood or they cantravel from brain metastases, carried by the cerebrospinal fluid (CSF)that flows through the meninges. In one embodiment the cancer isnon-metastatic cancer.

The anti-cancer treatment described in this specification may be usefulas a sole therapy, or may involve, in addition to administration of thecompound of Formula (I), conventional surgery, radiotherapy orchemotherapy; or a combination of such additional therapies. Suchconventional surgery, radiotherapy or chemotherapy may be administeredsimultaneously, sequentially or separately to treatment with thecompound of Formula (I).

Radiotherapy may include one or more of the following categories oftherapy:

-   -   i. External radiation therapy using electromagnetic radiation,        and intraoperative radiation therapy using electromagnetic        radiation;    -   ii. Internal radiation therapy or brachytherapy; including        interstitial radiation therapy or intraluminal radiation        therapy; or    -   iii. Systemic radiation therapy, including but not limited to        iodine 131 and strontium 89.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and radiotherapy,for use in the treatment of cancer. In one embodiment the cancer isglioblastoma. In one embodiment, the cancer is metastatic cancer. In oneembodiment the metastatic cancer comprises metastases of the centralnervous system. In one embodiment the metastases of the central nervoussystem comprise brain metastases. In one embodiment the metastases ofthe central nervous system comprise leptomeningeal metastases.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination withradiotherapy. In one embodiment the cancer is glioblastoma. In oneembodiment, the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and radiotherapy, for use inthe simultaneous, separate or sequential treatment of cancer. In oneembodiment the cancer is selected from glioblastoma, lung cancer (forexample small cell lung cancer or non-small cell lung cancer), breastcancer (for example triple negative breast cancer), head and necksquamous cell carcinoma, oesophageal cancer, cervical cancer andendometrial cancer. In one embodiment the cancer is glioblastoma. In oneembodiment, the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered simultaneously, separately orsequentially with radiotherapy. In one embodiment the cancer is selectedfrom glioblastoma, lung cancer (for example small cell lung cancer ornon-small cell lung cancer), breast cancer (for example triple negativebreast cancer), head and neck squamous cell carcinoma, oesophagealcancer, cervical cancer and endometrial cancer. In one embodiment thecancer is glioblastoma. In one embodiment, the cancer is metastaticcancer. In one embodiment the metastatic cancer comprises metastases ofthe central nervous system. In one embodiment the metastases of thecentral nervous system comprise brain metastases. In one embodiment themetastases of the central nervous system comprise leptomeningealmetastases.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and radiotherapy, where thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,and radiotherapy are jointly effective in producing an anti-cancereffect. In one embodiment the cancer is selected from glioblastoma, lungcancer (for example small cell lung cancer or non-small cell lungcancer), breast cancer (for example triple negative breast cancer), headand neck squamous cell carcinoma, oesophageal cancer, cervical cancerand endometrial cancer. In one embodiment the cancer is glioblastoma. Inone embodiment, the cancer is metastatic cancer. In one embodiment themetastatic cancer comprises metastases of the central nervous system. Inone embodiment the metastases of the central nervous system comprisebrain metastases. In one embodiment the metastases of the centralnervous system comprise leptomeningeal metastases.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and simultaneously,separately or sequentially administering radiotherapy, where thecompound of Formula (I), or a pharmaceutically acceptable salt thereof,and radiotherapy are jointly effective in producing an anti-cancereffect. In one embodiment the cancer is glioblastoma. In one embodiment,the cancer is metastatic cancer. In one embodiment the metastatic cancercomprises metastases of the central nervous system. In one embodimentthe metastases of the central nervous system comprise brain metastases.

In one embodiment the metastases of the central nervous system compriseleptomeningeal metastases.

In any embodiment the radiotherapy is selected from the group consistingof one or more of the categories of radiotherapy listed under points(i)-(iii) above.

Chemotherapy may include one or more of the following categories ofanti-tumour substance:

-   -   i. Antineoplastic agents and combinations thereof, such as DNA        alkylating agents (for example cisplatin, oxaliplatin,        carboplatin, cyclophosphamide, nitrogen mustards like        ifosfamide, bendamustine, melphalan, chlorambucil, busulphan,        temozolamide and nitrosoureas like carmustine); antimetabolites        (for example gemcitabine and antifolates such as        fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed,        methotrexate, cytosine arabinoside, and hydroxyurea);        anti-tumour antibiotics (for example anthracyclines like        adriamycin, bleomycin, doxorubicin, liposomal doxorubicin,        pirarubicin, daunomycin, valrubicin, epirubicin, idarubicin,        mitomycin-C, dactinomycin, amrubicin and mithramycin);        antimitotic agents (for example vinca alkaloids like        vincristine, vinblastine, vindesine and vinorelbine and taxoids        like taxol and taxotere and polokinase inhibitors); and        topoisomerase inhibitors (for example epipodophyllotoxins like        etoposide and teniposide, amsacrine, irinotecan, topotecan and        camptothecin); inhibitors of DNA repair mechanisms such as CHK        kinase; DNA-dependent protein kinase inhibitors; inhibitors of        poly (ADP-ribose) polymerase (PARP inhibitors, including        olaparib); and Hsp90 inhibitors such as tanespimycin and        retaspimycin, inhibitors of ATR kinase (such as AZD6738); and        inhibitors of WEE1 kinase (such as AZD1775/MK-1775);    -   ii. Antiangiogenic agents such as those that inhibit the effects        of vascular endothelial growth factor, for example the        anti-vascular endothelial cell growth factor antibody        bevacizumab and for example, a VEGF receptor tyrosine kinase        inhibitor such as vandetanib (ZD6474), sorafenib, vatalanib        (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib        (GW 786034) and cediranib (AZD2171); compounds such as those        disclosed in International Patent Applications WO97/22596, WO        97/30035, WO 97/32856 and WO 98/13354; and compounds that work        by other mechanisms (for example linomide, inhibitors of        integrin tv33 function and angiostatin), or inhibitors of        angiopoietins and their receptors (Tie-1 and Tie-2), inhibitors        of PLGF, inhibitors of delta-like ligand (DLL-4);    -   iii. Immunotherapy approaches, including for example ex-vivo and        in-vivo approaches to increase the immunogenicity of patient        tumour cells, such as transfection with cytokines such as        interleukin 2, interleukin 4 or granulocyte-macrophage colony        stimulating factor; approaches to decrease T-cell anergy or        regulatory T-cell function; approaches that enhance T-cell        responses to tumours, such as blocking antibodies to CTLA4 (for        example ipilimumab and tremelimumab), B7H1, PD-1 (for example        BMS-936558 or AMP-514), PD-L1 (for example MEDI4736) and agonist        antibodies to CD137; approaches using transfected immune cells        such as cytokine-transfected dendritic cells; approaches using        cytokine-transfected tumour cell lines, approaches using        antibodies to tumour associated antigens, and antibodies that        deplete target cell types (e.g., unconjugated anti-CD20        antibodies such as Rituximab, radiolabeled anti-CD20 antibodies        Bexxar and Zevalin, and anti-CD54 antibody Campath); approaches        using anti-idiotypic antibodies; approaches that enhance Natural        Killer cell function; and approaches that utilize antibody-toxin        conjugates (e.g. anti-CD33 antibody Mylotarg); immunotoxins such        as moxetumumab pasudotox; agonists of toll-like receptor 7 or        toll-like receptor 9;    -   iv. Efficacy enhancers, such as leucovorin.

Therefore, in one embodiment there is provided a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and at least oneadditional anti-tumour substance, for use in the treatment of cancer. Inone embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof is administered in combination with anadditional anti-tumour substance. In one embodiment there is oneadditional anti-tumour substance. In one embodiment there are twoadditional anti-tumour substances. In one embodiment there are three ormore additional anti-tumour substances.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance for use in the simultaneous, separate orsequential treatment of cancer. In one embodiment there is provided acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of cancer, where the compound of Formula (I),or a pharmaceutically acceptable salt thereof, is administeredsimultaneously, separately or sequentially with an additionalanti-tumour substance.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof and at least one additionalanti-tumour substance, where the amounts of the compound of Formula (I),or a pharmaceutically acceptable salt thereof, and the additionalanti-tumour substance are jointly effective in producing an anti-cancereffect.

In one embodiment there is provided a method of treating cancer in awarm-blooded animal who is in need of such treatment, which comprisesadministering to said warm-blooded animal a compound of Formula (I), ora pharmaceutically acceptable salt thereof, and simultaneously,separately or sequentially administering at least one additionalanti-tumour substance to said warm-blooded animal, where the amounts ofthe compound of Formula (I), or pharmaceutically acceptable saltthereof, and the additional anti-tumour to substance are jointlyeffective in producing an anti-cancer effect.

In any embodiment the additional anti-tumour substance is selected fromthe group consisting of one or more of the anti-tumour substances listedunder points (i)-(iv) above.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least oneanti-neoplastic agent for use in the treatment of cancer. In oneembodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone anti-neoplastic agent. In one embodiment the anti-neoplastic agentis selected from the list of antineoplastic agents in point (i) above.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least oneanti-neoplastic agent for use in the simultaneous, separate orsequential treatment of cancer. In one embodiment there is provided acompound of Formula (I), or a pharmaceutically acceptable salt thereof,for use in the treatment of cancer, where the compound of Formula (I),or a pharmaceutically acceptable salt thereof, is administeredsimultaneously, separately or sequentially with at least oneanti-neoplastic agent. In one embodiment the antineoplastic agent isselected from the list of antineoplastic agents in point (i) above.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of cisplatin,oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin,pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide,mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide,carmustine, melphalan, bleomycin, olaparib, MEDI4736, AZD1775 andAZD6738, for use in the treatment of cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of cisplatin,oxaliplatin, carboplatin, doxorubicin, pirarubicin, irinotecan,topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine,chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan,bleomycin, olaparib, AZD1775 and AZD6738, for use in the treatment ofcancer.

In one embodiment there is provided a compound of Formula (I), or a topharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin,doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin,etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide,ifosfamide, carmustine, melphalan, bleomycin, olaparib, MEDI4736,AZD1775 and AZD6738.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of doxorubicin,irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil,cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin andolaparib for use in the treatment of cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof doxorubicin, irinotecan, topotecan, etoposide, mitomycin,bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine,melphalan, bleomycin and olaparib.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least one additionalanti-tumour substance selected from the group consisting of doxorubicin,irinotecan, topotecan, etoposide, mitomycin, bendamustine, chlorambucil,cyclophosphamide, ifosfamide, carmustine, melphalan and bleomycin, foruse in the treatment of cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof doxorubicin, irinotecan, topotecan, etoposide, mitomycin,bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine,melphalan and bleomycin.

In one embodiment there is provided a compound of Formula (I), or a topharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with at leastone additional anti-tumour substance selected from the group consistingof doxorubicin, pirarubicin, amrubicin and epirubicin. In one embodimentthe cancer is acute myeloid leukaemia. In one embodiment the cancer isbreast cancer (for example triple negative breast cancer). In oneembodiment the cancer is hepatocellular carcinoma.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and irinotecan, for use in thetreatment of cancer. In one embodiment there is provided a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment of cancer, where the compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered in combinationwith irinotecan. In one embodiment the cancer is colorectal cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, and FOLFIRI, for use in thetreatment of cancer. In one embodiment there is provided a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment of cancer, where the compound of Formula (I), or apharmaceutically acceptable salt thereof, is administered in combinationwith FOLFIRI. In one embodiment the cancer is colorectal cancer.

FOLFIRI is a dosage regime involving a combination of leucovorin,5-fluorouracil and irinotecan.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with olaparib.In one embodiment the cancer is gastric cancer.

In one embodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with topotecan.In one embodiment the cancer is small cell lung cancer. In oneembodiment there is provided a compound of Formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofcancer, where the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is administered in combination with toimmunotherapy. In one embodiment the immunotherapy is one or more of theagents listed under point (iii) above. In one embodiment theimmunotherapy is an anti-PD-L1 antibody (for example MEDI4736).

According to a further embodiment there is provided a kit comprising:

a) A compound of formula (I), or a pharmaceutically acceptable saltthereof, in a first unit dosage form;

b) A further additional anti-tumour substance in a further unit dosageform;

c) Container means for containing said first and further unit dosageforms; and optionally

d) Instructions for use. In one embodiment the anti-tumour substancecomprises an anti-neoplastic agent.

In any embodiment where an anti-neoplastic agent is mentioned, theanti-neoplastic agent is one or more of the agents listed under point(i) above.

The compounds of Formula (I), and pharmaceutically acceptable saltsthereof, may be administered as pharmaceutical compositions, comprisingone or more pharmaceutically acceptable excipients.

Therefore, in one embodiment there is provided a pharmaceuticalcomposition comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.

The excipient(s) selected for inclusion in a particular composition willdepend on factors such as the mode of administration and the form of thecomposition provided. Suitable pharmaceutically acceptable excipientsare well known to persons skilled in the art and are described, forexample, in the Handbook of Pharmaceutical Excipients, Sixth edition,Pharmaceutical Press, edited by Rowe, Ray C; Sheskey, Paul J; Quinn,Marian. Pharmaceutically acceptable excipients may function as, forexample, adjuvants, diluents, carriers, stabilisers, flavourings,colorants, fillers, binders, disintegrants, lubricants, glidants,thickening agents and coating agents. As persons skilled in the art willappreciate, certain pharmaceutically acceptable excipients may servemore than one function and may serve alternative functions depending onhow much of the excipient is present in the composition and what otherexcipients are present in the composition.

The pharmaceutical compositions may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing), or as a suppository for rectal dosing. Thecompositions may be obtained by conventional procedures well known inthe art. Compositions intended for oral use may contain additionalcomponents, for example, one or more colouring, sweetening, flavouringand/or preservative agents.

The compound of Formula (I) will normally be administered to awarm-blooded animal at a unit dose within the range 2.5-5000 mg/m² bodyarea of the animal, or approximately 0.05-100 mg/kg, and this normallyprovides a therapeutically-effective dose. A unit dose form such as atablet or capsule will usually contain, for example 0.1-250 mg of activeingredient. The daily dose will necessarily be varied depending upon thehost treated, the particular route of administration, any therapiesbeing co-administered, and the severity of the illness being treated.Accordingly the practitioner who is treating any particular patient maydetermine the optimum dosage.

The pharmaceutical compositions described herein comprise compounds ofFormula (I), or a pharmaceutically acceptable salt thereof, and aretherefore expected to be useful in therapy.

As such, in one embodiment there is provided a pharmaceuticalcomposition for use in therapy, comprising a compound of Formula (I), ora pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.

In one embodiment there is provided a pharmaceutical composition for usein the treatment of a disease in which inhibition of ATM kinase isbeneficial, comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.

In one embodiment there is provided a pharmaceutical composition for usein the treatment of cancer, comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.

In one embodiment there is provided a pharmaceutical composition for usein the treatment of a cancer in which inhibition of ATM kinase isbeneficial, comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptableexcipient.

In one embodiment there is provided a pharmaceutical composition for usein the treatment of colorectal cancer, glioblastoma, gastric cancer,ovarian cancer, diffuse large B-cell lymphoma, chronic lymphocyticleukaemia, acute myeloid leukaemia, head and neck squamous cellcarcinoma, breast cancer, hepatocellular carcinoma, small cell lungcancer or non-small cell lung cancer, comprising a compound of Formula(I), or a pharmaceutically acceptable salt thereof, and at least onepharmaceutically acceptable excipient.

EXAMPLES

The various embodiments of the invention are illustrated by thefollowing Examples. The invention is not to be interpreted as beinglimited to the Examples. During the preparation of the Examples,generally:

-   -   i. Operations were carried out at ambient temperature, i.e. in        the range of about 17 to 30° C. and under an atmosphere of an        inert gas such as nitrogen unless otherwise stated;    -   ii. Evaporations were carried out by rotary evaporation or        utilising Genevac equipment in vacuo and work-up procedures were        carried out after removal of residual solids by filtration;    -   iii. Flash chromatography purifications were performed on an        automated Armen Glider Flash: Spot II Ultimate (Armen        Instrument, Saint-Ave, France) or automated Presearch combiflash        companions using prepacked Merck normal phase Si60 silica        cartridges (granulometry: 15-40 or 40-63 μm) obtained from        Merck, Darmstad, Germany, silicycle silica cartridges or        graceresolv silica cartridges;    -   iv. Preparative chromatography was performed on a Waters        instrument (600/2700 or 2525) fitted with a ZMD or ZQ ESCi mass        spectrometers and a Waters X-Terra or a Waters X-Bridge or a        Waters SunFire reverse-phase column (C-18, 5 microns silica, 19        mm or 50 mm diameter, 100 mm length, flow rate of 40 mL/minute)        using decreasingly polar mixtures of water (containing 1%        ammonia) and acetonitrile or decreasingly polar mixtures of        water (containing 0.1% formic acid) and acetonitrile as eluents;    -   v. Yields, where present, are not necessarily the maximum        attainable;    -   vi. Structures of end-products of Formula (I) were confirmed by        nuclear magnetic resonance (NMR) spectroscopy, with NMR chemical        shift values measured on the delta scale. Proton magnetic        resonance spectra were determined using a Bruker advance 700        (700 MHz), Bruker Avance 500 (500 MHz), Bruker 400 (400 MHz) or        Bruker 300 (300 MHz) instrument; 19F NMR were determined at 282        MHz or 376 MHz; 13C NMR were determined at 75 MHz or 100 MHz;        measurements were taken at around 20-30° C. unless otherwise        specified; the following abbreviations have been used: s,        singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,        doublet of doublets; ddd, doublet of doublet of doublet; dt,        doublet of triplets; bs, broad signal;    -   vii. End-products of Formula (I) were also characterised by mass        spectroscopy following liquid chromatography (LCMS); LCMS was        carried out using an Waters Alliance HT (2790 & 2795) fitted        with a Waters ZQ ESCi or ZMD ESCi mass spectrometer and an X        Bridge 5 m C-18 column (2.1×50 mm) at a flow rate of 2.4 mL/min,        using a solvent system of 95% A+5% C to 95% B+5% C over 4        minutes, where A=water, B=methanol, C=1:1 methanol:water        (containing 0.2% ammonium carbonate); or by using a Shimadzu        UFLC or UHPLC coupled with DAD detector, ELSD detector and 2020        EV mass spectrometer (or equivalent) fitted with a Phenomenex        Gemini-NX C18 3.0×50 mm, 3.0 μM column or equivalent (basic        conditions) or a Shim pack XR-ODS 3.0×50 mm, 2.2 μM column or        Waters BEH C18 2.1×50 mm, 1.7 μM column or equivalent using a        solvent system of 95% D+5% E to 95% E+5% D over 4 minutes, where        D=water (containing 0.05% TFA), E=Acetonitrile (containing 0.05%        TFA) (acidic conditions) or a solvent system of 90% F+10% G to        95% G+5% F over 4 minutes, where F=water (containing 6.5 mM        ammonium hydrogen carbonate and adjusted to pH10 by addition of        ammonia), G=Acetonitrile (basic conditions);    -   viii. Intermediates were not generally fully characterised and        purity was assessed by thin layer chromatographic, mass        spectral, HPLC and/or NMR analysis;    -   ix. X-ray powder diffraction spectra were determined (using a        Bruker D4 Analytical Instrument) by mounting a sample of the        crystalline material on a Bruker single to silicon crystal (SSC)        wafer mount and spreading out the sample into a thin layer with        the aid of a microscope slide. The sample was spun at 30        revolutions per minute (to improve counting statistics) and        irradiated with X-rays generated by a copper long-fine focus        tube operated at 40 kV and 40 mA with a wavelength of 1.5418        angstroms. The collimated X-ray source was passed through an        automatic variable divergence slit set at V20 and the reflected        radiation directed through a 5.89 mm antiscatter slit and a 9.55        mm detector slit. The sample was exposed for 0.03 seconds per        0.00570° 2-theta increment (continuous scan mode) over the range        2 degrees to 40 degrees 2-theta in theta-theta mode. The running        time was 3 minutes and 36 seconds. The instrument was equipped        with a Position sensitive detector (Lynxeye). Control and data        capture was by means of a Dell Optiplex 686 NT 4.0 Workstation        operating with Diffrac+software;    -   x. Differential Scanning Calorimetry was performed on a TA        Instruments Q1000 DSC. Typically, less than 5 mg of material        contained in a standard aluminium pan fitted with a lid was        heated over the temperature range 25° C. to 300° C. at a        constant heating rate of 10° C. per minute. A purge gas using        nitrogen was used at a flow rate 50 ml per minute    -   xi. The following abbreviations have been used: h=hour(s);        r.t.=room temperature (˜18-25° C.); conc.=concentrated;        FCC=flash column chromatography using silica;        DCM=dichloromethane; DIPEA=diisopropylethylamine;        DMA=N,N-dimethylacetamide; DMF=N,N-dimethylformamide;        DMSO=dimethylsulfoxide; Et₂O=diethyl ether; EtOAc=ethyl acetate;        EtOH=ethanol; K₂CO₃=potassium carbonate; MeOH=methanol;        MeCN=acetonitrile; MTBE=Methyltertbutylether; MgSO₄=anhydrous        magnesium sulphate; Na₂SO₄=anhydrous sodium sulphate;        THF=tetrahydrofuran; sat.=saturated aqueous solution; and    -   xii. IUPAC names were generated using either “Canvas” or ‘IBIS’,        AstraZeneca proprietary programs. As stated in the introduction,        the compounds of the invention comprise an        imidazo[4,5-c]quinolin-2-one core. However, in certain Examples        the IUPAC name describes the core as an        imidazo[5,4-c]quinolin-2-one. The imidazo[4,5-c]quinolin-2-one        and imidazo[5,4-c]quinolin-2-one cores are nevertheless the        same, with the naming convention different because of the        peripheral groups.

Example 18-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one

3-(Dimethylamino)propan-1-ol (0.433 mL, 3.66 mmol) was added slowly to aslurry of sodium hydride (0.333 g, 8.33 mmol) in THF (10 mL) and thesolution stirred at 0° C. for 30 minutes. The solution was added to asolution of7-fluoro-8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one(1.18 g, 3.33 mmol) in THF (20 mL). The reaction was stirred at r.t. for24 h and quenched with water. The solvent was removed under reducedpressure and extracted with DCM (2×100 mL). The organics were washedwith water (50 mL), dried over a phase separator and the solvent removedunder reduced pressure to afford crude product. The crude product waspurified by flash silica chromatography, elution gradient 0 to 10% MeOHin DCM, to afford the desired material. The solid was heated in MeCN (15mL) and allowed to cool to r.t. overnight. The white solid was filteredunder vacuum and dried in a vacuum oven for 3 h to afford the desiredmaterial as a white solid (1.79 g, 41%). NMR Spectrum: ¹H NMR (500 MHz,DMSO-d6) δ 1.65 (6H, d), 1.90 (2H, p), 2.17 (6H, s), 2.38 (2H, t), 3.50(3H, s), 4.38 (2H, t), 5.29 (1H, hept), 6.99 (1H, dd), 7.92 (1H, d),8.05 (1H, dt), 8.33 (1H, d), 8.50 (1H, dd), 8.91 (1H, s).

¹H NMR (500 MHz, CDCl₃) δ 1.76 (6H, d), 1.96-2.06 (2H, m), 2.28 (6H, s),2.44-2.51 (2H, m), 3.58 (3H, s), 4.44 (2H, t), 5.22 (1H, s), 6.89 (1H,dd), 7.86-7.92 (2H, m), 8.21 (1H, d), 8.41 (1H, d), 8.69 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=438.

The desired material can also be isolated as the methane sulfonic acidsalt as described below: 1M Methanesulfonic acid in DCM (0.660 mL, 0.66mmol) was added portionwise to isolated free base (275 mg, 0.63 mmol) inDCM (5 mL) at ambient temperature over a period of 1 minute. Theresulting solution was stirred at ambient temperature for 1 h thenconcentrated in vacuo and the residue dried under vacuum to afford thedesired methanesulfonic acid salt as a white solid (336 mg, 100%). NMRSpectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.65 (6H, d), 2.05-2.21 (2H, m),2.32 (3H, s), 2.76 (6H, s), 3.04-3.21 (2H, m), 3.51 (3H, s), 4.43 (2H,t), 5.29 (1H, hept), 7.02 (1H, dd), 7.93 (1H, d), 8.09 (1H, dt), 8.32(1H, d), 8.53 (1H, dd), 8.92 (1H, s), 9.36 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=438.

Intermediate A1:7-Fluoro-8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one

Dichlorobis(di-tert-butyl(3-sulfopropyl)phosphonio)palladate(II) (0.05Msolution in water, 11.83 mL, 0.59 mmol) was added to a degassed mixtureof 8-bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one(4.0 g, 11.83 mmol), (6-fluoropyridin-3-yl)boronic acid (2.0 g, 14.19mmol) and 2M potassium carbonate solution (17.74 mL, 35.48 mmol) in1,4-dioxane (50 mL) and water (12.5 mL). The mixture was purged withnitrogen and heated to 80° C. for 1 h then allowed to cool andconcentrated under reduced pressure to remove. The remaining solutionwas diluted with DCM (250 mL), washed with water (200 mL) and theorganic layer dried with a phase separating cartridge and evaporated toafford crude product. The crude product was purified by flash silicachromatography, elution gradient 0 to 10% MeOH in DCM, to afford thedesired material as a white solid (3.70 g, 88%). NMR Spectrum: ¹H NMR(500 MHz, CDCl₃) δ 1.77 (6H, dd), 3.58 (3H, d), 5.20 (1H, s), 7.11 (1H,ddd), 7.93 (1H, d), 8.06-8.14 (1H, m), 8.22 (1H, d), 8.46-8.51 (1H, m),8.72 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=355.3.

Dichlorobis(di-tert-butyl(3-sulfopropyl)phosphonio)palladate(II) (0.05Msolution in water) can be prepared as described below:

Degassed water (30 mL) was added to sodium tetrachloropalladate(II)(0.410 g, 1.39 mmol) and 3-(di-tert-butylphosphino)propane-1-sulfonicacid (0.748 g, 2.79 mmol) at ambient temperature under an inertatmosphere. The suspension was stirred for 5 minutes, then the solidremoved by filtration and discarded to leave the desired reagent as ared-brown solution.

Intermediate A2:8-Bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one

A solution of sodium hydroxide (11.29 g, 282.28 mmol) in water (600 mL)was added to a stirred mixture of8-bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one (61 g,188.19 mmol), tetrabutylammonium bromide (6.07 g, 18.82 mmol) and methyliodide (23.53 mL, 376.37 mmol) in DCM (1300 mL) and the mixture stirredat ambient temperature for 17 h. The same process was repeated on anidentical scale and the reaction mixtures combined, concentrated anddiluted with MeOH (750 mL). The precipitate was collected by filtration,washed with MeOH (500 mL) and the solid dried under vacuum to afford thedesired material as a white solid (108 g, 85%). NMR Spectrum: ¹H NMR(400 MHz, CDCl₃) δ 1.76 (6H, d), 3.57 (3H, s), 5.13 (1H, t), 7.83 (1H,d), 8.41 (1H, d), 8.69 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=380.

Intermediate A3:8-Bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one

Triethylamine (164 mL, 1173.78 mmol) was added in one portion to6-bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxylic acid (128 g,391.26 mmol) in DMF (1500 mL) and the mixture stirred at ambienttemperature under an inert atmosphere for 30 minutes. Diphenylphosphorylazide (101 mL, 469.51 mmol) was added and the solution stirred for afurther 30 minutes at ambient temperature then 3 h at 60° C. Thereaction mixture was poured into ice water, the precipitate collected byfiltration, washed with water (1 L) and dried under vacuum to afford thedesired material as a yellow solid (122 g, 96%). NMR Spectrum: ¹H NMR(400 MHz, DMSO-d6) δ 1.62 (6H, d), 5.12-5.19 (1H, m), 7.92 (1H, d), 8.57(1H, d), 8.68 (1H, s), 11.58 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=324.

8-Bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one can also beprepared as described below.

1,3,5-Trichloro-1,3,5-triazinane-2,4,6-trione (5.91 g, 25.45 mmol) wasadded portionwise to a stirred suspension of6-bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxamide (16.6 g,50.89 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (15.22 mL, 101.79mmol) in methanol (200 mL) at 5° C. The resulting suspension was stirredat ambient temperature for 1 h. The reaction was filtered and the soliddried in a vacuum oven for 2 h to afford the desired material as a paleyellow solid (14.18 g, 86%). Additional material was obtained afterleaving the filtrate to stand for 2 days and then filtering. Theadditional solid isolated was heated in EtOH (50 mL) for 30 minutes thenallowed to cool and filtered to provide additional desired material as awhite solid (2.6 mg). Analytical data was consistent with that obtainedfrom alternative preparations described earlier.

A large scale preparation of8-bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one was alsocarried out as follows.6-Bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxylic acid (3.910kg, 11.15 mol, 93.3 mass %) was charged to a vessel under nitrogen,followed by DMF (22 L). The resulting slurry was stirred andtriethylamine (4.7 L) added over 2 min. The resulting mixture wasstirred at 21-23° C., then warmed to 56° C. Diphenyl phosphoryl azide(2.9 L, 13 mol, 99.5 mass %) was added over 1 h, keeping the temperatureof the mixture in the range 56-61° C. by varying the rate of additionand the jacket set point (exothermic addition—jacket set point 50-57°C.). The addition vessel was rinsed through into the reactor with DMF(0.75 L) and the reaction mixture stirred at 55° C. for 1 h, thenanalysed by HPLC which indicated completion of the reaction to give theintermediate compound8-bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one.N,N-Dimethylformamide dimethyl acetal (7.29 L, 54.4 mol, 99.2 mass %)was then added to over 5 min, and the mixture warmed to 100°C.—precipitation was observed when the temperature reached 94° C. andthe stirring rate was increased from 150 to 300 r.p.m. The mixture wasstirred for 24 h at 100° C. and analysed by HPLC which indicated 1.2%area of the intermediate (target <0.5% area of intermediate) heating wascontinued at 99° C. for a further 16 h after which time the reaction wasadjudged to have reached a satisfactory level of completion (0.45% areaof intermediate remaining). The mixture was then cooled to 22° C. andwater (23 L) added over 25 min. keeping the temperature below 30° C.(jacket set initially to 0-5° C. for the first part of the additionwhich is exothermic—vessel contents kept in the range 22-26° C.throughout the addition). The resulting slurry was stirred at 25-26° C.for 50 min. then filtered and washed with twice with water (11.2 and11.5 L) that was added to the filter cake via the reaction vessel. Thecollected solid was sucked dry on the filter for 1 h then transferred toa vacuum oven and dried in vacuo at 60° C. for approx.26 h to give thedesired product (3.445 kg, 9.41 mol, 92.4 mass %, 84.4% Yield).

Intermediate A4:6-Bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxylic acid

2N Sodium hydroxide solution (833 mL, 1666.66 mmol) was addedportionwise to ethyl6-bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxylate (148 g,416.66 mmol) in THF (1500 mL) at 15° C. and the resulting mixturestirred at 60° C. for 5 h. The reaction mixture was concentrated,diluted with water (2 L) and the mixture acidified with 2M hydrochloricacid. The precipitate was collected by filtration, washed with water (1L) and dried under vacuum to afford the desired material as a whitesolid (128 g, 94%). NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.24-1.36(6H, m), 4.37 (1H, s), 7.78 (1H, t), 8.55 (1H, s), 8.90 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=327.

6-Bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxylic acid was alsoprepared on a larger scale according to the following procedure. Astirred suspension of ethyl6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (4 kg, 12.00 mol, 99.8mass %) in THF (24 L) was heated to 52° C. under an atmosphere ofnitrogen. Isopropyl amine (2.10 L, 25.60 mol, 99.9 mass %) was thenadded over 1 h 30 min. The temperature rose to 54° C. afterapproximately half of the isopropyl amine was added, the addition waspaused, cooling applied, and addition resumed when the temperature hadfallen to 48° C. The addition vessel was rinsed with THF (4 L) and therinse added to the reaction mixture. The mixture was stirred for 18.5 hat 50° C. and then analysed by HPLC which indicated approx. 4% of thestarting chloroester remaining (target <0.5%). Further isopropyl amine(150 mL, 1.830 mol, 99.9 mass %) was added and mixture stirrer for afurther 22.5 h by which time the reaction was adjudged to have gone tocompletion. Sodium hydroxide solution (1.99M in water; 13.3 L, 26.50mol) was charged to the mixture over 5 min. to give a pale yellowmixture that was heated to 60° C. and stirred at this temperature for22.5 h, then analysed by HPLC that indicated satisfactory completion ofthe ester hydrolysis. The mixture was cooled to 18° C. then dischargedfrom the vessel to a receiver vessel and recharged back to the reactionvessel via an inline filter. THF (12 L) was charged to the receiver andtransferred to the reactor via the inline filter. The vessel jackettemperature was set to 15° C. and Phosphoric acid (1.250 L, 85 mass %)added over 1 h; the temperature of the mixture was 17-18° C. during theaddition, resulting in precipitation of the crude product. The resultingslurry was stirred for 20 h at 20° C., then filtered and washed withwater (2×20 L) that was added to the filter cake via the reactionvessel. The collected solid was sucked dry on the filter thentransferred to a vacuum oven and dried in vacuo at 60° C. for approx. 52h to give the desired product (3.935 Kg, 11.22 mol, 93.3 mass %, 93.5%Yield).

Intermediate A5: Ethyl6-bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxylate

DIPEA (154 mL, 884.07 mmol) was added portionwise to propan-2-amine(39.2 g, 663.05 mmol) and ethyl6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate (147 g, 442.04 mmol) inDMA (600 mL) at ambient temperature and the resulting mixture stirred at100° C. for 4 h. The reaction mixture was poured into ice water, theprecipitate collected by filtration, washed with water (1 L) and driedunder vacuum to afford the desired material as a light brown solid (148g, 94%). NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.26-1.33 (9H, m),4.17-4.25 (1H, m), 4.32-4.37 (2H, m), 7.28 (1H, d), 8.50 (1H, d), 8.59(1H, d), 8.86 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=355.

Intermediate A6: Ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate

DMF (0.535 mL, 6.91 mmol) was added to ethyl6-bromo-7-fluoro-1-[(4-methoxyphenyl)methyl]-4-oxo-quinoline-3-carboxylate(200 g, 460.56 mmol) in thionyl chloride (600 mL) at 10° C. under aninert atmosphere and the resulting mixture stirred at 70° C. for 3 h.The mixture was evaporated to dryness and the residue azeotroped withtoluene (300 mL) to afford crude product. The crude product was purifiedby crystallisation from hexane to afford the desired material as a whitesolid (147 g, 96%). NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.49 (3H,t), 4.51-4.56 (2H, m), 7.91 (1H, d), 8.71 (1H, d), 9.26 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=334.

Ethyl 6-bromo-4-chloro-7-fluoroquinoline-3-carboxylate was also preparedon a larger scale according to the following procedure. DMF (0.235 L,2.56 mol) was added to ethyl6-bromo-7-fluoro-1-[(4-methoxyphenyl)methyl]-4-oxo-quinoline-3-carboxylate(13.53 kg, 30.43 mol, 97.7 mass %) in toluene (90 L) under an inertatmosphere. The resulting suspension was stirred and heated to 88° C.over 48 minutes. A solution of thionyl chloride (3.32 L, 45.7 mol) intoluene (1.65 L) was then added to the mixture over 4 h 10 min.,maintaining the temperature of the mixture in the range 89-91° C. Themixture was held at 89° C. for 50 minutes then analysed by HPLC whichindicated completion of the reaction (no starting material detected).The mixture was cooled to 20° C. over 1 h and held overnight at thistemperature. The mixture was discharged from the reaction vessel and thevessel rinsed with toluene (13 L). The rinse was added to the mainbatch. The batch was split into two equal halves and the first halftreated as follows: it was evaporated to dryness over approx.5 h on a 50L rotary evaporator (batch added in portions as evaporation progressed,bath temperature 60° C., vacuum set point 50 mbar) and the residuetreated with to heptane (13.2 L) and evaporated (bath temperature 60°C., vacuum set point 100 mbar). The heptane treatment (13.2 L) wasrepeated to give a thick slurry that was diluted by the portion wiseaddition of further heptane (53 L) and the heptane slurry transferredportion wise to a clean vessel. The second half of the toluene mixturewas worked up in the same way and combined with the first half to give aslurry of the crude product in heptane (approximately 106 L). Theheptane slurry was heated to 91° C. over 2 h 20 min. by which time thecrude product had dissolved; the mixture was then transferred to aclean, pre-heated (jacket set point 90° C.) vessel via an inline filterto remove particulates. A line wash of heptane (5 L) was then appliedvia the source vessel. Vacuum (450 mbar) was applied to the destinationvessel and heptane (46 L) removed by distillation (batch temperature77-78° C., head temperature 72-73° C.). The vacuum was released withnitrogen and the vessel contents cooled to 49° C. over 45 min, resultingin crystallisation of the product. The slurry was held 48-49° C. for 30min. then cooled to 20° C. over 1 h and held at 20° C. overnight. Theslurry was filtered, and the source vessel rinsed with heptane (14 L)for 5 mins, then the rinse was applied as a wash to the product cake. Afurther rinse and wash of heptane (14 L) was then applied and the cakesucked dry over 1 h. The collected solid was transferred to a vacuumoven and dried in vacuo at 50° C. to afford the desired material as anoff-white solid (8.915 kg, 26.75 mol, 99.8 mass %, 87.9% Yield).

Intermediate A7: Ethyl6-bromo-7-fluoro-1-[(4-methoxyphenyl)methyl]-4-oxo-quinoline-3-carboxylate

DBU (76 mL, 506.32 mmol) was added slowly toethyl-2-(5-bromo-2,4-difluoro-benzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate(230 g, 506.32 mmol) in acetone (800 mL) at 10° C. over a period of 5minutes under an inert atmosphere and the resulting mixture stirred atambient temperature for 16 h. The precipitate was collected byfiltration, washed with Et₂O (3×500 mL) and dried under vacuum to affordthe desired material as a white solid (166 g, 75%). NMR Spectrum: ¹H NMR(400 MHz, DMSO-d6) δ 1.29 (3H, t), 3.72 (3H, s), 4.22-4.27 (21H, m),5.57 (2H, s), 6.92-6.95 (2H, m), 7.24 (2H, d), 7.79 (1H, d), 8.40 (1H,d), 8.89 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=434.

Intermediate A8:Ethyl-2-(5-bromo-2,4-difluoro-benzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate

(E)-Ethyl 3-(dimethylamino)acrylate (80 mL, 555.50 mmol) was addeddropwise to a mixture of DIPEA (132 mL, 757.50 mmol) and5-bromo-2,4-difluoro-benzoyl chloride (129 g, 505.00 mmol) in toluene(600 mL) at ambient temperature under an inert atmosphere. The resultingsolution was stirred at 70° C. for 17 h then allowed to cool.(4-Methoxyphenyl)methanamine (66.0 mL, 505.29 mmol) was addedportionwise to the mixture and the reaction stirred for 3 h at ambienttemperature. The reaction mixture was diluted with DCM (2 L), washedsequentially with water (4×200 mL), saturated brine (300 mL), theorganic layer dried over Na₂SO₄, filtered and evaporated to afford thedesired material as a light brown solid (230 g, 100%) which was used inthe next step without further purification. NMR Spectrum: ¹H NMR (400MHz, CDCl₃) δ 1.09 (3H, t), 3.82 (3H, s), 4.00-4.10 (2H, m), 4.55 (2H,t), 6.84-6.96 (3H, m), 7.20-7.29 (2H, m), 7.55 (1H, d), 8.18 (1H, t).Mass Spectrum: m/z (ES+)[M+H]+=454.

Intermediate A9: 5-Bromo-2,4-difluoro-benzoyl chloride

Thionyl chloride (55.4 mL, 759.50 mmol) was added portionwise to amixture of DMF (7.84 mL, 101.27 mmol) and 5-bromo-2,4-difluorobenzoicacid (120 g, 506.33 mmol) in toluene (600 mL) at 15° C. over a period of5 minutes under an inert atmosphere. The resulting mixture was stirredat 70° C. for 4 h then evaporated to dryness and the residue wasazeotroped with toluene to afford the desired material as a brown oil(129 g, 100%) which was used directly in the next step withoutpurification. NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 7.04-7.09 (1H, m),8.34-8.42 (1H, m).

Intermediate A10:6-Bromo-7-fluoro-4-(isopropylamino)quinoline-3-carboxamide

Propan-2-amine (2.80 ml, 32.62 mmol) was added to a suspension of6-bromo-4-chloro-7-fluoro-quinoline-3-carboxamide (10 g, 29.65 mmol) andpotassium carbonate (8.20 g, 59.31 mmol) in acetonitrile (250 mL) andthe mixture stirred at 95° C. for 4 h. Further propan-2-amine (2 mL) wasadded and the mixture stirred at 95° C. for another 4 h then at ambienttemperature overnight. Water was added to the mixture and the solidcollected by filtration and dried under vacuum to afford the desiredmaterial (8.25 g, 85%). NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.25(6H, d), 4.17 (1H, d), 7.51 (1H, s), 7.69 (1H, d), 8.11 (2H, s), 8.61(1H, s), 8.67 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=236.

Intermediate A11: 6-Bromo-4-chloro-7-fluoro-quinoline-3-carboxamide

DMF (0.5 mL) was added to a stirred suspension of6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic acid (22.5 g, 78.66mmol) in thionyl chloride (140 g, 1179.85 mmol) and the mixture heatedto reflux for 2 h. The reaction was allowed to cool, concentrated invacuo and the residue azeotroped twice with toluene to afford a yellowsolid. This solid was added portionwise to a solution of ammoniumhydroxide (147 mL, 1179.85 mmol) at 0° C. The white suspension wasstirred for 15 minutes then the solid filtered, washed with water anddried under vacuum to afford the desired material (23.80 g, 100%) as awhite powder. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 8.92 (1H, s),8.59 (1H, d), 8.21 (1H, s), 8.09 (1H, d), 7.98 (1H, s). Mass Spectrum:m/z (ES+)[M+H]+=304.8.

Intermediate A12: 6-Bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylic acid

A solution of sodium hydroxide (18.34 g, 458.44 mmol) in water (100 mL)was added to a stirred suspension of ethyl6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate (28.8 g, 91.69 mmol)in EtOH (500 mL) at ambient temperature. The reaction mixture was thenstirred at 75° C. for 2 h, allowed to cool and the pH adjusted to 4using 2N hydrochloric acid. The precipitate was collected by filtration,washed with water and dried under vacuum to afford the desired material(23.30 g, 89%) as a white powder. NMR Spectrum: ¹H NMR (400 MHz,DMSO-d6) δ 14.78 (1H, s), 13.45 (1H, s), 8.93 (1H, s), 8.46 (1H, d),7.70 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=287.8.

Intermediate A13: Ethyl6-bromo-7-fluoro-4-oxo-1H-quinoline-3-carboxylate

A solution of diethyl2-[(4-bromo-3-fluoro-anilino)methylene]propanedioate (90 g, 249.88 mmol)in diphenyl ether (600 mL, 3.79 mol) was stirred at 240° C. for 2.5 h.The mixture was allowed to cool to 70° C., the solids collected byfiltration and dried in a vacuum oven to afford the desired material (50g, 64%) as a white solid which was used without further purification.NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6, (100° C.)) δ 1.26-1.33 (3H, m),4.25 (2H, q), 7.52 (1H, d), 8.37 (1H, d), 8.48 (1H, s), 12.05 (1H, s).Mass Spectrum: m/z (ES+)[M+H]+=314.

Intermediate A14: Diethyl2-[(4-bromo-3-fluoro-anilino)methylene]propanedioate

A solution of 4-bromo-3-fluoroaniline (56.6 g, 297.87 mmol) and1,3-diethyl 2-(ethoxymethylidene)propanedioate (72.45 g, 335.06 mmol) inEtOH (560 mL) was stirred at 80° C. for 4 h. The reaction mixture wasallowed to cool, the solids collected by filtration and dried in an ovento afford the desired material (90 g, 84%) as an off-white solid whichwas used without further purification. NMR Spectrum: ¹H NMR (400 MHz,DMSO-d6) δ 1.26 (6H, q), 4.14 (2H, q), 4.22 (2H, q), 7.18-7.25 (1H, m),7.57 (1H, dd), 7.64-7.7 (1H, m), 8.33 (1H, d), 10.62 (1H, d). MassSpectrum: m/z (ES+)[M+H]+=360.

8-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-onecan also be prepared directly from8-bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one usingthe method described below. 3-(Di-tert-butylphosphino)propane-1-sulfonicacid (0.467 mg, 1.77 mmol) was added to monopalladium(IV) disodiumtetrachloride (0.261 g, 0.89 mmol) in water (50 mL) under an inertatmosphere. The resulting mixture was stirred at ambient temperature for20 minutes, then the reaction mixture was added in one portion to8-bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one,N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(42.4 g, 110.89 mmol) and potassium carbonate (36.8 g, 266.13 mmol) indioxane (500 mL) and water (100 mL) at ambient temperature under aninert atmosphere. The resulting solution was stirred at 80° C. for 2 h.The reaction solution was concentrated under vacuum and diluted withDCM. The organic phase was dried over Na₂SO₄, filtered and evaporated toafford to crude product. The crude was purified by silica, elutiongradient 0 to 2% MeOH (7M ammonia in MeOH) in DCM, to afford a solidwhich was triturated with MeCN to afford the desired material as ayellow solid (25.00 g, 64.4%). The pure material was combined withadditional material prepared in an analogous fashion (38.6 g total) andwas heated in MeCN (100 mL) for 10 min then allowed to cool to 0° C. andstirred for 2 h. The solid was filtered under vacuum and dried in avacuum oven for 16 h to afford the desired material as a pale yellowcrystalline solid (35.5 g). The analytical data was consistent with thatfrom material prepared previously.

Intermediate B1:N,N-Dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine

n-Butyllithium (2.5 M, 0.147 L, 368.21 mmol) was added dropwise to3-(5-bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (73.4 g, 283.24mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (68.5 g,368.21 mmol) in THF (1 L) cooled to −78° C. over a period of 10 minutesunder an inert atmosphere. The resulting mixture was allowed to warm toambient temperature and stirred for 2 h. The reaction mixture wasquenched with a saturated aqueous solution of ammonium chloride (50 mL).The solvent was removed under reduced pressure and diluted with EtOAc (2L), the organic layer was dried over Na₂SO₄, filtered and evaporated toafford the desired material as a yellow oil (98 g, 113%). The productwas used in the next step directly without further purification. NMRSpectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.30 (12H, s), 1.93-2.09 (2H, m),2.33 (6H, s), 2.49-2.61 (2H, m), 4.37 (2H, t), 6.69 (1H, dd), 7.91 (1H,dd), 8.51 (1H, d).

Intermediate B2: 3-(5-Bromopyridin-2-yl)oxy-N,N-dimethylpropan-1-amine

Sodium hydride (17.05 g, 426.17 mmol) was added portionwise to3-(dimethylamino)propan-1-ol (35.2 g, 340.94 mmol) in THF (500 mL) at 5°C. and the mixture allowed to warm to ambient temperature.5-Bromo-2-fluoropyridine (50 g, 284.11 mmol) was added and the solutionstirred at 50° C. for 2 h. The reaction solution was added carefully toice-water and the aqueous phase was extracted with DCM (3×700 mL). Theorganic phase was dried over Na₂SO₄, filtered and evaporated to affordthe desired material as a yellow oil (73.6 g, 100%). The material wasused without further purification. NMR Spectrum: ¹H NMR (300 MHz, CDCl₃)δ 1.92-2.01 (2H, m), 2.28 (6H, s), 2.45 (2H, t), 4.33 (2H, t), 6.67 (1H,dd), 7.65 (1H, dd), 8.20 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=259.

Example 27-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one

3-(Piperidin-1-yl)propan-1-ol (1.051 g, 7.34 mmol) in THF (15 mL) wasadded slowly to a slurry of sodium hydride (0.587 g, 14.67 mmol) in THF(15 mL) and the solution stirred at 50° C. for 40 minutes. A mixture of7-fluoro-8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one(2.0 g, 5.64 mmol) in THF (15 mL) was added and the reaction stirred for6 h at 50° C. then allowed to cool to r.t. and quenched with water.Solid precipitation was observed upon standing and was collected byfiltration. The material was purified by flash silica chromatography,elution gradient 0 to 10% MeOH in DCM, then by preparative HPLC (redisepgold C18 column, 80 g), using decreasingly polar mixtures of water(containing 0.1% ammonia) and MeCN as eluents, to afford the desiredmaterial. The product was recrystallized from boiling EtOH to afforddesired material as a white solid (1.512 g, 56.1%). NMR Spectrum: ¹H NMR(500 MHz, DMSO-d6) δ 1.34-1.44 (2H, m), 1.50 (4H, p), 1.65 (6H, d), 1.91(2H, p), 2.29-2.37 (4H, m), 2.39 (2H, q), 3.51 (3H, s), 4.37 (2H, t),5.29 (1H, p), 6.99 (1H, dd), 7.92 (1H, d), 8.05 (1H, dt), 8.33 (1H, d),8.50 (1H, s), 8.91 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=478.

The desired material can also be isolated as the methane sulfonic acidsalt as follows. Methanesulfonic acid (0.026 g, 0.27 mmol) in DCM (0.5mL) was added to the isolated free base (127 mg, 0.27 mmol) at ambienttemperature. The resulting solution was stirred at ambient temperaturefor 15 minutes then concentrated in vacuo and the residue dried undervacuum to afford the desired methanesulfonic acid salt as a white solid(336 mg, 100%). NMR Spectrum: ¹H NMR (500 MHz, CDCl₃) δ 1.78 (6H, d),1.86-1.99 (4H, m), 2.11-2.25 (2H, m), 2.37-2.48 (2H, m), 2.6-2.74 (2H,m), 2.84 (3H, s), 3.22-3.31 (2H, m), 3.59 (3H, s), 3.69 (2H, d),4.48-4.56 (2H, m), 5.17-5.27 (1H, m), 6.90 (1H, dd), 7.90 (1H, dt), 7.96(1H, d), 8.23 (1H, d), 8.39 (1H, d), 8.76 (1H, s), 10.75 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=478.

7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onecan also be prepared directly from8-bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one usingthe method described below.

3-(Di-tert-butylphosphino)propane-1-sulfonic acid (0.555 mg, 2.07 mmol)was added to monopalladium(IV) disodium tetrachloride (0.304 g, 1.03mmol) in water (12 mL) under an inert atmosphere. The resulting mixturewas stirred at ambient temperature for 10 minutes, then the reactionmixture was added in one portion to8-bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one (35.0g, 103.50 mmol),2-[3-(1-piperidyl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(62.2 g, 129.37 mmol) and potassium carbonate (42.9 g, 310.49 mmol) indioxane (450 mL) and water (90 mL) at ambient temperature under an inertatmosphere. The resulting solution was stirred at 80° C. for 16 h andthe reaction evaporated. The crude material was dissolved in DCM (500mL), was washed with brine (2×100 mL), the organic phase dried overNa₂SO₄, filtered and evaporated. The crude product was purified by flashsilica chromatography, elution gradient 0 to 10% (0.1% ammonia in MeOH)in DCM, to afford the desired material as a brown solid (40.5 g, 82%).The material was combined with material obtained from analogouspreparations (total 51.3 g) and slurried in MeCN (100 mL). Theprecipitate was collected by filtration, washed with MeCN (100 mL) anddried under vacuum to the desired material as a white solid (32.0 g,62.4%). The analytical data was consistent with that from previouslyprepared samples.

The material obtained from the MeCN slurry was found to be crystallineform A of Example 2. Example 2 Form A is characterised in providing anX-ray powder diffraction pattern substantially as shown in FIG. 1. TenX-Ray powder diffraction peaks are shown in Table 1.

TABLE 1 Characteristic X-Ray powder diffraction peaks for Form A ofExample 2, 7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one Angle 2- Theta (2θ) Intensity %3.7 100 14.8 77 18.4 57 21.0 56 11.3 44 19.4 34 22.3 34 18.0 33 23.2 3013.1 30

Example 2 Form A displays a melting endotherm with an onset of 141.5° C.and a peak at 144.2° C. when analysed by differential scanningcalorimetry (DSC) at a scanning rate of 10° C./mins (FIG. 2).

A further method of preparing7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-oneis as follows. A 250 mL flask was purged with nitrogen three times.Sodium tetra-chloropalladate (2.51 g, 8.5 mmol.),3-(di-tert-butylphosphino)propane-1-sulfonic acid (4.36 g, 16.2 mmol.)and water (95 mL) were charged. The phosphine ligand mixture was left tostir under nitrogen at room to temperature for 10 minutes. A 10 L flangeflask was purged with nitrogen three times.8-Bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one(281.3 g, 0.83 mol.),2-[3-(1-piperidyl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(360.0 g, 1.04 mol.), potassium carbonate (347.2 g. 2.51 mol.), dioxane(3.6 L, 12.9 vol.) and water (720 mL, 2.6 vol.) were charged to theflange flask. The pre-mixed phosphine ligand catalyst mixture wasquickly charged into the reaction mixture (10 L flange flask) undernitrogen. The reaction mixture was then heated at 80° C. under nitrogenatmosphere and monitored by HPLC. After 2 h, analysis showed thereaction was complete with low level (0.30%) of starting materialremaining. The reaction mixture was cooled to room temperature (20° C.)under nitrogen then concentrated under reduced pressure. The resultantresidue was taken up in DCM (4 L, 14.3 vol.) forming a dark brown/greensolution. The solution was washed with saturated brine solution (2×780mL), and the organic layer was separated off. The aqueous layer was backextracted with dichloromethane (1250 mL, 4.5 vol.), and the combinedorganic layer was filtered to remove a green solid precipitate (assumedto be catalyst related impurities), before it was dried over sodiumsulphate (782.7 g) and concentrated under vacuum to give adichloromethane wet yellow solid. The crude material was dried undervacuum in an oven at 40° C. overnight, to give a 492.7 g (335.0 gactive) of crude product. Analysis indicated the material was 95.0% pureby HPLC and 68% active by NMR Assay. The second batch was completed onthe same scale to obtain a further 494.2 g (326.2 g active) of crudeproduct. Analysis indicated the material was 88.0% pure by HPLC and 66%active by NMR Assay. The two batches were combined to give a total crudemass of 968.4 g (661 g active) which was passed through silica (12 kg)using an eluent gradient mixture of DCM with methanol (0-40%) andammonia (0-0.2%), (total solvent usage: 285 litres). The productcontaining fractions (>97% by liquid chromatography) were combined andconcentrated under vacuum, slurried in methanol (2 volumes) overnightand dried under vacuum at 50° C. to give a white solid, 392.9 g, 49.5%yield. The product containing fractions (<97% by liquid chromatography)were combined and concentrated under vacuum and slurried in ethylacetate for 2 h. The resulting solid was then slurried in methanol (2vol) to give an additional 111.3 g of product. Both batches werecombined and slurried in heptane (5 vol.) for 1 h 30 min, beforefiltering and drying under vacuum in an oven at 50° C. overnight. Thisgave a total yield of 487.2 g (61%) with a purity of 96% by ¹H NMRassay.

The material obtained from the preparation above was found to becrystalline form B of Example 2. Example 2 Form B is characterised inproviding an X-ray powder diffraction pattern substantially as shown inFIG. 3. Ten X-Ray powder diffraction peaks are shown in Table 2.

TABLE 2 Characteristic X-Ray powder diffraction peaks for Form B ofExample 2, 7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one Angle 2- Theta (2θ) Intensity %3.4 42 11.7 67 22.7 100 13.5 64 13.1 45 19.0 42 23.4 30 24.0 21 17.5 1818.1 15

Example 2 Form B displays a melting endotherm with an onset of 144.7° C.and a peak at 145.8° C. when analysed by differential scanningcalorimetry (DSC) at a scanning rate of 10° C./mins (FIG. 4).

7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-onecan be prepared on a large scale using the following procedure. Under anatmosphere of nitrogen,8-bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one (0.800 kg,2.31 mol, 97.6 mass %) was charged to a vessel followed by2-[3-(1-piperidyl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.879 kg, 2.54 mol) and potassium carbonate (0.960 kg, 6.95 mol). THF(8 L) and water (3.9 L) were then added and stirring of the mixtureinitiated. Vacuum was gradually applied until the THF just started toboil (135 mbar) and then released with nitrogen. The vacuum purgeprocedure was repeated twice more (approx. 0.5 L THF lost to receiver)and a slow trickle of nitrogen applied to the vessel.Dichloro[1,1′-bis(di-tertbutylphosphino)ferrocene]palladium(II) (Pd-118,15 g, 0.023 mol) was added via a glove bag and the mixture heated to63-64° C. and held at this temperature for 2 h then analysed by HPLCwhich indicated acceptable conversion to the desired product. Themixture was cooled to 20° C., stirring was stopped and the mixtureallowed to separate and the lower aqueous phase run off to waste. Asolution of brine made up from water (3.45 L) and sodium chloride (0.586kg) was charged to the organic phase in the vessel and the mixturestirred for 10 mins then allowed to separate. The aqueous phase was runoff to waste and the organic phase filtered through a bed of celite (150g). The vessel was rinsed with THF (800 mL) and the rinse put throughthe celite cake and added to the organic filtrate. The combined THFfiltrate (ca. 9.5 L) was charged to a clean vessel and metal scavengingaid Phosphonics SPM 32 (780 g) added. The mixture was stirred at 21° C.for 16 h then filtered to remove the insoluble scavenging aid. A rinseof THF (1.6 L) was applied to the reactor vessel and passed through thefilter. The combined filtrate and rinse were then transferred to a cleanvessel and solvent (6.9 L) distilled off at reduced pressure (23-24° C.,150 mbar). Isopropanol (11 L) was added to the residue in the reactor,and a further amount of solvent (9.2 L) removed by distillation atreduced pressure (40-43° C. batch temperature, 150 mbar). Theconcentrated mixture in the vessel was heated to 80° C. and stirringrate increased to wash down and dissolve product that had been observedto crystallise on the vessel walls. The hot solution was transferred viaan in-line filter to a clean dry, pre-heated (jacket temperature 80° C.)receiving vessel, equipped with a Lasentec FBRM probe. The transferredsolution was cooled to 60° C. and seeded with the desired product (FormB, 0.44 g) and stirred at 58-60° C. for 5 h, then cooled to 20° C. over14 h to crystallise the product. The slurry was sampled and analysed byXRPD that indicated it to be a mixture of polymorphs (Form B and FormA—major component). The mixture was heated to 48-50° C. and re-sampledand adjudged to be still a mixture of polymorphs. The slurry was thendiluted with isopropanol (1.5 L) and stirred and heated at 50° C. forapprox. 67 h by which time the amount of the desired Form B hadincreased to approx. 50%. 2 L of the mixture was removed to performlaboratory studies and the remaining bulk of the slurry then heated at56° C. for a further approx. 21 h by which time it had converted to FormB. The slurry was then cooled to 10° C. over 20 h and held at 10-11° C.for approx. 5 h then filtered. A wash ofisopropanol (2.2 L) was appliedto the product cake via the crystallisation vessel. The cake was suckeddry for 20 mins on the filter and then dried in vacuo at 50° C. forapproximately 22 h to afford the desired product as its Form Bpolymorph, (824 g, 1.729 mol, 100 mass %, 74.9% Yield).

Intermediate C1:2-[3-(1-piperidyl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

n-Butyllithium (139 mL, 347.59 mmol) was added dropwise to5-bromo-2-[3-(1-piperidyl)propoxy]pyridine (80 g, 267.37 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (64.7 g, 347.59mmol) in THF (400 mL) cooled to −78° C. over a period of 10 minutesunder an inert atmosphere. The resulting mixture was allowed to warm toambient temperature and stirred for 12 h. The reaction mixture wasquenched with a saturated aqueous solution of ammonium chloride (100 mL)and the mixture concentrated under reduced pressure. The mixture wasextracted with EtOAc (2×500 mL), the organic layer washed with saturatedbrine (2×100 mL), dried over Na₂SO₄, filtered and evaporated to affordthe desired material as a yellow oil (92 g, 99%). The to product wasused in the next step directly without further purification. NMRSpectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.34 (12H, s), 1.60 (5H, p),1.93-2.08 (3H, m), 2.39-2.53 (6H, m), 4.34 (2H, dt), 6.67-6.77 (1H, m),7.92 (1H, dd), 8.50-8.56 (1H, m).

Intermediate C2: 5-Bromo-2-[3-(1-piperidyl)propoxy]pyridine

Sodium hydride (20.91 g, 522.77 mmol) was added portionwise to3-(piperidin-1-yl)propan-1-ol (35.8 g, 250.02 mmol) in THF (400 mL) atambient temperature under an inert atmosphere. The resulting suspensionwas stirred at 50° C. for 30 minutes then allowed to cool and5-bromo-2-fluoropyridine (40.0 g, 227.29 mmol) added. The solution wasstirred at 50° C. for 2 h then allowed to cool. The reaction wasrepeated in analogues fashion using sodium hydride (5.23 g, 130.69mmol), 3-(piperidin-1-yl)propan-1-ol (8.95 g, 62.50 mmol), THF (100 mL)and 5-bromo-2-fluoropyridine (10 g, 56.82 mmol). The two reactionmixtures were combined and poured into ice/water (1000 mL). The solventwas concentrated under reduced pressure and extracted with DCM (3×150mL), the organic layer was washed with saturated brine (3×150 mL), driedover Na₂SO₄, filtered and evaporated to afford the desired material as abrown oil (96 g, 113%). The material was used without furtherpurification. NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.43-1.49 (2H, m),1.61 (5H, p), 1.99 (2H, dq), 2.46 (6H, dd), 4.31 (2H, t), 6.65 (1H, d),7.64 (1H, dd), 8.19 (1H, d). Mass Spectrum: m/z (ES+)[M+H]+=299.

Example 37-Fluoro-1-isopropyl-3-methyl-8-[6-(3-pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2-one

3-(Pyrrolidin-1-yl)propan-1-ol (62.0 mg, 0.48 mmol) was added to sodiumhydride (13.54 mg, 0.56 mmol) in THF (5 mL) at r.t. under an inertatmosphere and the reaction stirred for 20 minutes.7-Fluoro-8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one(100 mg, 0.28 mmol) was added and the reaction stirred for 16 h. Thereaction mixture was quenched with saturated NH₄Cl (15 mL), extractedwith DCM (3×15 mL), the organic layer dried over Na₂SO₄, filtered andevaporated to afford crude product. The crude product was purified bypreparative HPLC (XSelect CSH Prep C18 OBD column, 5μ silica, 19 mmdiameter, 150 mm length), using decreasingly polar mixtures of water(containing 0.1% Formic acid) and MeCN as eluents, to afford the desiredmaterial as a white solid (85 mg, 61.9%). NMR Spectrum: ¹H NMR (300 MHz,CDCl₃) δ 1.78 (6H, d), 1.99-2.10 (4H, m), 2.31 (2H, dt), 3.03-3.15 (6H,m), 3.59 (3H, s), 4.47 (2H, t), 5.23 (1H, s), 6.85-6.94 (1H, m),7.85-7.97 (2H, m), 8.21 (1H, d), 8.41 (1H, s), 8.71 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=464.

The following compound was prepared in an analogous fashion.

Example Structure Name 4

8-[6-[3-(azetidin-1-yl)propoxy]-3- pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2- one

Example 4

NMR Spectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.75-1.78 (6H, s), 2.08-2.15(2H, q), 2.40-2.50 (2H, m), 3.08-3.14 (2H, m), 3.59 (3H, s), 3.87-3.92(4H, t), 4.42-4.46 (2H, t), 5.18-5.26 (1H, m), 6.88-6.91 (1H, m),7.87-7.93 (2H, m), 8.21 (1H, d), 8.41 (1H, s), 8.71 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=450.

Intermediate D1: 3-(Azetidin-1-yl)propan-1-ol

A solution of lithium aluminium hydride (2.0 M in THF) (8.38 mL, 16.76mmol) diluted in further THF (20 mL) was added to a mixture of methyl3-(azetidin-1-yl)propanoate (2 g, 13.97 mmol) in THF (5 mL) dropwise at0° C. under an inert atmosphere. The resulting solution was stirred at0° C. for 1 h then the reaction mixture treated with sodium sulphatedecahydrate and stirred for 30 minutes. The solid was removed byfiltration and discarded and the filtrate evaporated to afford thedesired material (1.240 g, 77%) as a colourless oil. NMR Spectrum: ¹HNMR (400 MHz, CDCl₃) δ 1.51-1.57 (2H, m), 2-2.07 (2H, m), 2.6-2.66 (2H,m), 3.20 (4H, t), 3.7-3.76 (2H, m).

Intermediate D2: Methyl 3-(azetidin-1-yl)propanoate

Methyl acrylate (2.082 ml, 23.12 mmol) was added to a solution ofazetidine (1.2 g, 21.02 mmol) in DCM and the resulting solution stirredat ambient temperature, under an inert atmosphere for 16 h. The reactionmixture was evaporated and the crude product purified by FCC, elutedwith 25% EtOAc in DCM, to afford the desired material (2.0 g, 66.5%) asa colourless oil. NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.97-2.1 (2H,m), 2.33 (2H, d), 2.67 (2H, d), 3.18 (4H, t), 3.67 (3H, s).

Example 51-Isopropyl-3-methyl-8-[6-[3-(l-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one

3-(Piperidin-1-yl)propan-1-ol (0.135 mL, 0.89 mmol) was added dropwiseto a stirred suspension of sodium hydride (0.071 g, 1.78 mmol) in THF(0.5 mL) at r.t. and the resulting suspension stirred at r.t. for 10minutes under an inert atmosphere.8-(6-Fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one(0.15 g, 0.45 mmol) in DMF (1.5 mL) was added and the reaction mixturestirred at r.t. for one h. The reaction mixture was diluted with ethylacetate (40 mL), washed twice with water (20 mL) then the organic slayer dried over MgSO₄, filtered and evaporated to afford crude product.The crude product was purified by flash silica chromatography, elutiongradient 0 to 3% 2N methanolic ammonia in DCM, to afford the desiredmaterial as a white solid (0.154 g, 75%). NMR Spectrum: ¹H NMR (500 MHz,CDCl₃) δ 1.39-1.51 (2H, m), 1.60 (4H, p), 1.79 (6H, d), 2.03 (2H, dt),2.42 (4H, s), 2.47-2.58 (2H, m), 3.59 (3H, s), 4.42 (2H, t), 5.19-5.41(1H, m), 6.89 (1H, d), 7.78 (1H, dd), 7.90 (1H, dd), 8.22 (1H, d), 8.32(1H, s), 8.50 (1H, d), 8.70 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=460.

The above material can also be isolated as the methane sulfonic acidsalt by taking the material as prepared above and subjecting to thefollowing reaction conditions.

1-Isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one(133 mg, 0.29 mmol) was dissolved in DCM (2 mL) and treated with 1Mmethanesulfonic acid (0.3 mL, 0.30 mmol) in DCM then the mixtureevaporated to dryness. The residue was triturated with diethyl ether toafford the methane sulfonic acid salt as a pale yellow solid (162 mg).NMR Spectrum: ¹H NMR (500 MHz, CDCl₃) δ 1.31-1.5 (1H, m), 1.68 (9H, d),1.83 (2H, d), 2.13-2.26 (2H, m), 2.32 (3H, s), 2.84-3.01 (2H, m), 3.24(2H, dt), 3.52 (5H, s), 4.43 (2H, t), 5.38 (1H, p), 7.00 (1H, d), 7.99(1H, d), 8.17 (1H, d), 8.24 (1H, dd), 8.43 (1H, s), 8.69 (1H, d), 8.95(1H, s), 9.04 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=460.

The following compounds were prepared in an analogous fashion fromeither8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-oneor7-fluoro-8-(6-fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-oneand the appropriate alcohol.

Example Structure Name 6

8-[6-[3- (dimethylamino)propoxy]-3- pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one 7*

1-isopropyl-3-methyl-8-[6-(3- pyrrolidin-1-ylpropoxy)-3-pyridyl]imidazo[4,5-c]quinolin-2- one *Reaction stirred for 2 h at r.t.

Example 6

(Free base) NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.68 (6H, d), 1.89(2H, p), 2.16 (6H, s), 2.37 (2H, t), 3.51 (3H, s), 4.37 (2H, t), 5.36(1H, p), 6.98 (1H, dd), 7.93 (1H, dd), 8.14 (1H, d), 8.18 (1H, dd), 8.40(1H, d), 8.66 (1H, dd), 8.88 (1H, s). (Methane sulfonic acid salt) NMRSpectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.68 (6H, d), 2.07-2.25 (2H, m),2.33 (3H, s), 2.80 (6H, s), 3.15-3.24 (2H, m), 3.51 (3H, s), 4.42 (2H,t), 5.35 (1H, p), 7.00 (1H, dd), 7.94 (1H, dd), 8.15 (1H, d), 8.23 (1H,dd), 8.40 (1H, d), 8.68 (1H, dd), 8.89 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=420.

Example 7

(Free base) NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.61-1.77 (10H,m), 1.93 (2H, p), 2.43-2.49 (4H, m), 2.53-2.59 (2H, m), 3.51 (3H, s),4.38 (2H, t), 5.29-5.43 (1H, m), 6.97 (1H, dd), 7.93 (1H, dd), 8.13 (1H,d), 8.18 (1H, dd), 8.40 (1H, d), 8.65 (1H, dd), 8.88 (1H, s). (Methanesulfonic acid salt) NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.68 (6H,d), 1.88 (4H, s), 2.11-2.23 (2H, m), 2.32 (3H, s), 3.08 (2H, s), 3.32(2H, s), 3.51 (3H, s), 3.60 (2H, s), 4.44 (2H, t), 5.36 (1H, p), 7.01(1H, d), 7.94 (1H, dd), 8.15 (1H, d), 8.23 (1H, dd), 8.40 (1H, d), 8.68(1H, d), 8.89 (1H, s), 9.50 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=446.

Intermediate E1:8-(6-Fluoro-3-pyridyl)-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one

8-Bromo-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one (4.57 g, 14.27mmol), (6-fluoropyridin-3-yl)boronic acid (2.61 g, 18.55 mmol) and 2Mpotassium carbonate (22 mL, 44.00 mmol) were suspended in 1,4-dioxane(90 mL). The mixture was degassed thendichloro[1,1′-bis(di-tertbutylphosphino)ferrocene] palladium(II) (0.465g, 0.71 mmol) added and the reaction to 80° C. for 2 h under an inertatmosphere. The mixture was allowed to cool, diluted with EtOAc (200 mL)then washed with water (50 mL), brine, and the organic phase dried overMgSO₄, filtered and concentrated in vacuo. The crude product waspurified by flash silica chromatography, elution gradient 0 to 5% MeOHin DCM, to afford material which was subsequently triturated withdiethyl ether to afford the desired material as an off-white solid (4.46g, 93%). NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.66 (6H, d), 3.50(3H, s), 5.36 (1H, p), 7.36 (1H, dd), 7.95 (1H, dd), 8.15 (1H, d),8.39-8.52 (2H, m), 8.72 (1H, d), 8.90 (1H, s). Mass Spectrum: m/z(ES+)[M+H]+=337.

Intermediate E2:8-Bromo-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one

N,N-Dimethylformamide dimethyl acetal (54.2 mL, 408.29 mmol) was addedto a solution of 8-bromo-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one(25.00 g, 81.66 mmol) in DMF (375 mL). The mixture was heated to 80° C.for 3 h then allowed to cool to ambient temperature and stirred for 16h. The precipitate was collected by filtration, washed with water (4×300mL) and dried under vacuum at 50° C. to afford the desired material as awhite solid (23.82 g, 91%). NMR Spectrum: ¹H NMR (500 MHz, DMSO-d6) δ1.63 (6H, d), 3.49 (3H, s), 5.15-5.23 (1H, m), 7.75 (1H, dd), 7.99 (1H,d), 8.44 (1H, d), 8.91 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=320.

Intermediate E3: 8-Bromo-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one

Triethylamine (45.3 mL, 332.06 mmol) was added to6-bromo-4-(isopropylamino)quinoline-3-carboxylic acid (34.22 g, 110.69mmol) in DMF (342 mL) at ambient temperature. After stirring at ambienttemperature for 30 minutes, diphenyl phosphorazidate (26.2 mL, 121.76mmol) was added and the resulting mixture stirred at 60° C. for 2 h. Thereaction mixture was poured into water (1500 mL); the precipitatecollected by filtration, washed with water (2×700 mL) and dried undervacuum at 50° C. to afford the desired material as a beige solid (29.6g, 87%), which was used without further purification. NMR Spectrum: ¹HNMR (500 MHz, CDCl₃) δ 1.64 (6H, d), 5.06-5.21 (1H, m), 7.75 (1H, d),7.98 (1H, d), 8.43 (1H, s), 8.69 (1H, s), 11.57 (1H, s).

Mass Spectrum: m/z (ES+)[M+H]+=306.

Intermediate E4: 6-Bromo-4-(isopropylamino)quinoline-3-carboxylic acid

Ethyl 6-bromo-4-(isopropylamino)quinoline-3-carboxylate (38.0 g, 112.69mmol) was suspended in methanol (800 mL) and water (200 mL). 10M sodiumhydroxide solution (33.8 mL, 338.07 mmol) was added and the mixturestirred at ambient temperature for 1 h. THF (200 mL) was added and theresultant mixture stirred for 16 h. Water (400 mL) was added and theorganics removed under reduced pressure. The resulting aqueous solutionwas acidified to pH 4-5 with 2M HCl and the precipitate collected byfiltration, washed with water and dried under vacuum to afford thedesired material as a white solid (34.7 g, 100%). NMR Spectrum: ¹H NMR(500 MHz, DMSO-d6) δ 1.33 (6H, d), 4.39 (1H, s), 7.78 (1H, d), 7.92 (1H,dd), 8.38 (1H, d), 8.88 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=309.

Intermediate E5: Ethyl 6-bromo-4-(isopropylamino)quinoline-3-carboxylate

Propan-2-amine (11.00 ml, 128.02 mmol) was added to a suspension ofethyl 6-bromo-4-chloroquinoline-3-carboxylate (36.61 g, 116.38 mmol) andpotassium carbonate (32.2 g, 232.77 mmol) in acetonitrile (250 mL) at 0°C. The mixture was stirred at 54° C. under reflux for 3 h. Furtherpotassium carbonate (10.7 g, 77.6 mmol) and propan-2-amine (3.6 ml, 42.7mmol) were added and stirring continued at 48° C. for a further 16 h.The solvents were removed in vacuo and the resulting residue partitionedbetween DCM (400 mL) and water (500 mL). The aqueous layer wasre-extracted with DCM (2×200 mL); the combined organic layers werepassed through a phase separating paper and concentrated under reducedpressure to afford the desired material as a beige solid (38.6 g, 98%).NMR Spectrum: ¹H NMR (500 MHz, CDCl₃) δ 1.40 (6H, d), 1.43 (3H, t),4.32-4.37 (1H, m), 4.40 (2H, q), 7.72 (1H, dd), 7.81 (1H, d), 8.29 (1H,d), 8.95 (1H, d), 9.10 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=337.

Intermediate E6: Ethyl 6-bromo-4-chloroquinoline-3-carboxylate

DMF (0.119 mL, 1.54 mmol) was added to ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (160 g,384.37 mmol) in thionyl chloride (800 mL) at ambient temperature underair. The resulting mixture was stirred at 75° C. for 16 h then thesolvent removed under reduced pressure. The resulting mixture wasazeotroped twice with toluene then n-hexane (500 mL) added. Theprecipitate was collected by filtration, washed with n-hexane (200 mL)and dried under vacuum to afford the desired material (100 g, 83%) as abrown solid. NMR Spectrum: ¹H NMR (400 MHz, CDCl₃) δ 1.47 (3H, t), 4.51(2H, q), 7.95 (1H, dd), 8.11 (1H, d), 8.60 (1H, d), 9.24 (1H, s). MassSpectrum: m/z (ES+)[M+H]+=314, 316.

On a larger scale, ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate (5765g, 13.85 mol) was charged to the vessel with thionyl chloride (28.8 L).An exotherm from 20-26° C. was observed. DMF (4.4 mL) was added with noobserved exotherm and the batch heated to 75° C. and stirred for 17 h.HPLC showed 1.3% starting material remained with 98.0% product. Thereaction was concentrated in vacuo and the residue azeotroped withtoluene (25 L). The resulting solid was then slurried in heptane to(18.5 L) for 2.5 h, filtered and washed with heptane (3×4 L). The solidwas dried under vacuum at 35° C. to give 4077 g of the desired material(93% crude yield) which contained ˜5% of ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate inaddition to ˜4% hydrolysis product by HPLC (90% pure). The crudematerial (4077 g) was returned to the vessel and reprocessed withthionyl chloride (14.5 L) and DMF (2.2 mL). The mixture was heated to75° C. for 40 h. The thionyl chloride was removed in vacuo and theresidue azeotroped with toluene (10 L). The residue was slurried inheptane (18 L) for ˜16 h at 20° C. The solid was collected byfiltration, one portion being filtered under nitrogen and washed withheptane (3 L) to yield 2196 g of desired material (90% NMR assay, 99% byHPLC). The remainder of the batch was filtered under air and washed withheptane (3 L) to yield 1905 g of the desired material (88% NMR assay,99% by HPLC). The yellow solids were combined for further processing(4101 g, 3653 g active, 83% yield, 99% by HPLC).

Intermediate E7: Ethyl6-bromo-1-[(4-methoxyphenyl)methyl]-4-oxoquinoline-3-carboxylate

DBU (102 mL, 679.62 mmol) was added drop-wise to ethyl2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate(296.5 g, 679.62 mmol), in acetone (1.2 L) at ambient temperature over aperiod of 2 minutes. The resulting solution was stirred for 16 h thenthe solid removed by filtration and washed with MTBE to afford thedesired material (180 g, 64%) as light yellow solid. NMR Spectrum: ¹HNMR (400 MHz, DMSO-d6) δ 1.30 (3H, t), 3.71 (3H, s), 4.25 (2H, q), 5.60(2H, s), 6.90-6.95 (2H, m), 7.12-7.25 (2H, m), 7.67 (1H, d), 7.80-7.90(1H, m), 8.30 (1H, d), 8.92 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=418.

On a larger scale, ethyl2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate(8434 g, (7730 g assumed active), 17.71 mol) was charged to the vesselwith acetone (23.2 L) at 15° C. DBU (2.8 L, 18.72 mol) was added over 25minutes with an observed exotherm from 18-23° C. over the addition. Aprecipitate formed after ˜25 minutes and the batch continued to exothermreaching a maximum of 37° C. after 1 h. The reaction was stirred at 20°C. for 16.5 h at which point HPLC indicated consumption of startingmaterial and 96.5% product. The resulting precipitate was collected byfiltration washing with TBME (4×3.4 L). The solid was then dried undervacuum at 40° C. to give 6033 g of the desired material as a white solid(81.6% yield over 3 steps, 99.8% purity by HPLC). Analytical data wasconsistent with that obtained on previous batches.

Intermediate E8: Ethyl2-(5-bromo-2-fluorobenzoyl)-3-[(4-methoxyphenyl)methylamino]prop-2-enoate

(E)-Ethyl 3-(dimethylamino)acrylate (98 g, 685.00 mmol) was addedportion-wise to 5-bromo-2-fluorobenzoyl chloride (163 g, 685 mmol) andDIPEA (120 mL, 685.00 mmol) in toluene (800 mL) at 10° C. over a periodof 10 minutes. The resulting solution was stirred at 70° C. for 16 hthen allowed to cool. (4-Methoxyphenyl)methanamine (94 g, 685 mmol) wasadded to the mixture over a period of 20 minutes at ambient temperature.The resulting solution was stirred for 3 h then the reaction mixturediluted with DCM (4 L), and washed with water (3×1 L). The organic phasewas dried over Na₂SO₄, filtered and evaporated to give the desiredmaterial (300 g, 100%) as brown oil, which was used immediately in thesubsequent reaction without further purification. Mass Spectrum: m/z(ES+)[M+H]+=436.

On a larger scale, 5-bromo-2-fluorobenzoyl chloride (4318 g, 4205 gactive, 17.71 mol) was charged to the vessel as a solution in toluene(7.5 L). DIPEA (3150 mL, 18.08 mol) was added with no observed exotherm.Ethyl-3-(dimethylamino)acrylate (2532 g, 17.71 mol) was addedportionwise over 30 minutes maintaining a batch temperature <40° C. Anexotherm from 21-24° C. was noted over the 30 minute addition with afurther slow rise to to 38° C. over 1 h. The reaction was stirred at20-30° C. for 16.5 h. 4-Methoxybenzylamine (2439 g, 17.78 mol) was addedportionwise over 30 mins maintaining a batch temperature <40° C. Anexotherm of 25-30° C. was observed over the addition with coolingprovided by a reduced jacket temperature of 15° C. The reaction wasstirred for 4 h at 20-30° C. after which HPLC indicated 93.2% of desiredmaterial. The batch was split for workup with each half of the mixturediluted with DCM (28.6 L) and washed with water (3×7.8 L). The organicswere dried over MgSO₄ (˜550 g) and filtered, washing with DCM (4 L). Thecombined organics were then concentrated to give 8444 g of the desiredmaterial as an oil (8434 g, 106% yield, 94.7% purity by HPLC).Analytical data was consistent with that obtained from previous batches.

Intermediate E9: 5-Bromo-2-fluorobenzoyl chloride

Thionyl chloride (75.0 mL, 1027.36 mmol) was added drop-wise to5-bromo-2-fluorobenzoic acid (150 g, 684.91 mmol), in toluene (1.2 L)and DMF (12 mL) at ambient temperature over a period of 1 h. Theresulting mixture was stirred at 70° C. for 16 h then the mixtureallowed to cool and concentrated in vacuo to afford the desired material(160 g, 98%) as light yellow oil, which was used without furtherpurification. NMR Spectrum: ¹H NMR (400 MHz, DMSO-d6) δ 7.26-7.31 (1H,m), 7.83 (1H, dd), 8.02 (1H, d). On a larger scale,3-bromo-6-fluorobenzoic acid (3888 g, 17.75 mol) was charged to thevessel at 20° C. followed by toluene (29.2 L). Thionyl chloride (1950ml, 26.88 mol) was added, followed by DMF (310 mL) with no observedexotherm. The mixture was heated to 65-75° C. (solution obtained above˜45° C.) with no observed exotherm and slight gas evolution. Thereaction was stirred for 40 h at this temperature at which point HPLCanalysis showed 87.6% product, 3.4% starting material. The reaction wasconcentrated in vacuo and azeotroped with toluene (18 L) to give 4328 gof the desired material (103% yield, 87.3% by HPLC).

Example 88-[6-[3-(Azetidin-1-yl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (24.55 mg, 0.03 mmol) wasadded to 8-bromo-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one (100mg, 0.31 mmol),2-(3-(azetidin-1-yl)propoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(149 mg, 0.47 mmol) and cesium carbonate (204 mg, 0.62 mmol) in1,4-dioxane (4 mL), water (1 mL) at r.t. under an inert atmosphere. Theresulting mixture was stirred at 100° C. for 2 h then allowed to cooland the solvent removed under reduced pressure. The crude product waspurified by preparative HPLC (XSelect CSH Prep C18 OBD column, 5.silica, 19 mm diameter, 150 mm length), using decreasingly polarmixtures of water (containing 0.1% Formic acid) and MeCN as eluents, toafford the desired material as a white solid (30.0 mg, 21%). NMRSpectrum: ¹H NMR (400 MHz, DMSO-d6) δ 1.72 (8H, dd), 1.97 (2H, p), 2.50(2H, s), 3.14 (4H, dd), 3.51 (3H, s), 4.34 (2H, t), 5.36 (1H, p), 6.97(1H, d), 7.94 (1H, dd), 8.10-8.23 (2H, m), 8.40 (1H, d), 8.66 (1H, d),8.89 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=432.

Intermediate F1:2-[3-(Azetidin-1-yl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

n-Butyl lithium (4.65 mL, 11.62 mmol) was added to2-[3-(azetidin-1-yl)propoxy]-5-bromopyridine (2.1 g, 7.74 mmol) and2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.161 g, 11.62mmol) in THF (50 mL) at −78° C. over a period of 10 minutes and theresulting solution stirred at −78° C. for 1 h. The reaction was quenchedwith sat. aqueous solution of sodium hydrogen carbonate (10 mL) and thesolvent removed in vacuo. The residue was dissolved in DCM (100 mL),dried over Na₂SO₄, filtered and to evaporated to afford the desiredmaterial (2.00 g, 81%) as a white solid.

Mass Spectrum: m/z (ES+)[M+H]+=319

Intermediate F2: 2-[3-(Azetidin-1-yl)propoxy]-5-bromopyridine

Sodium hydride (1.364 g, 56.82 mmol) was added to3-(azetidin-1-yl)propan-1-ol (2.62 g, 22.73 mmol) in THF (20 mL) atambient temperature under an inert atmosphere and the reaction stirredfor 10 minutes. 5-Bromo-2-fluoropyridine (2.0 g, 11.36 mmol) was addedand the resulting solution stirred for 1 h before being quenched withwater (20 mL) and extracted with EtOAc (5×50 mL). The organics werecombined, dried over Na₂SO₄, filtered and concentrated in vacuo toafford the desired material (3.75 g, 122%) as a white solid. NMRSpectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.80 (2H, m), 2.11 (2H, m), 2.55(2H, t), 3.18 (4H, t), 4.328 (2H, t), 6.64 (1H, d), 7.62 (1H, dd), 8.16(1H, d). Mass Spectrum: m/z (ES+)[M+H]+=271.

Example 98-[2-Fluoro-6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (45.6 mg, 0.06 mmol) was addedto2-fluoro-6-[3-(1-piperidyl)propoxy]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(crude reaction mixture assumed to contain 232 mg, 0.64 mmol),8-bromo-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one (186 mg, 0.58mmol) and cesium carbonate (567 mg, 1.74 mmol) in 1,4-dioxane (5 mL) andwater (2.5 mL). The resulting mixture was stirred at 80° C. for three hthen allowed to cool. The reaction mixture was diluted with ethylacetate (50 mL), washed twice with water (25 mL), the organic layerdried over MgSO₄, filtered and evaporated to afford crude product. Thecrude product was purified by flash silica chromatography, elutiongradient 0 to 4% 2N methanolic ammonia in DCM, to afford the desiredmaterial as an off-white solid (168 mg, 61%). NMR Spectrum: ¹H NMR (500MHz, DMSO-d6) δ 1.37 (2H, d), 1.48 (4H, p), 1.64 (6H, d), 1.88 (2H, p),2.22-2.44 (6H, m), 3.49 (3H, s), 4.30 (2H, t), 5.26 (1H, h), 6.93 (1H,dd), 7.80 (1H, dd), 8.12 (1H, d), 8.21 (1H, dd), 8.42 (1H, s), 8.89 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=478.

The above material can also be isolated as the methane sulfonic acidsalt by taking the material as prepared above and subjecting to thefollowing reaction conditions.8-[2-Fluoro-6-[3-(1-piperidyl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one(162 mg, 0.34 mmol) was dissolved in DCM (4 mL) and treated with 1Mmethanesulfonic acid (0.35 mL, 0.36 mmol) in DCM then the mixtureevaporated to dryness. The residue was triturated with diethyl ether toafford the methane sulfonic acid salt as a white solid (184 mg). NMRSpectrum: ¹H NMR (500 MHz, DMSO-d6) δ 1.22-1.98 (12H, m), 2.06-2.24 (2H,m), 2.31 (3H, s), 2.90 (2H, s), 3.19 (2H, s), 3.50 (5H, s), 4.37 (2H,t), 5.25 (1H, p), 6.96 (1H, d), 7.80 (1H, d), 8.13 (1H, d), 8.26 (1H,dd), 8.42 (1H, s), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=478.

The following compounds were prepared in an analogous fashion fromeither 8-bromo-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one or8-bromo-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin-2-one andthe appropriate boronic ester.

Example Structure Name 10*

8-[6-[3- (dimethylamino)propoxy]-2- fluoro-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5-c]quinolin- 2-one 11*

8-[6-[3- (dimethylamino)propoxy]-2- fluoro-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5- c]quinolin-2-one 12**

8-[2-fluoro-6-(3-pyrrolidin-1- ylpropoxy)-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5- c]quinolin-2-one 13**

7-fluoro-8-[2-fluoro-6-(3- pyrrolidin-1-ylpropoxy)-3-pyridyl]-1-isopropyl-3-methyl- imidazo[4,5-c]quinolin-2-one 14***

7-fluoro-8-[2-fluoro-6-[3-(1- piperidyl)propoxy]-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5- c]quinolin-2-one 15***

8-[6-[3-(azetidin-1-yl)propoxy]- 2-fluoro-3-pyridyl]-1-isopropyl-3-methyl-imidazo[4,5- c]quinolin-2-one 16****

8-[6-[3-(azetidin-1-yl)propoxy]- 2-fluoro-3-pyridyl]-7-fluoro-1-isopropyl-3-methyl-imidazo[4,5- c]quinolin-2-one *The reaction wasstirred at 80° C. for 5 h and purified by flash column chromatographyand/or preparative HPLC. **The reaction was stirred at 80° C. for 5 h ina 5:1 mixture of dioxane/water, and purified by flash columnchromatography followed? by preparative HPLC. ***The reaction wasstirred at 80° C. for 2 h in a 4:1 mixture of dioxane/water, ****Thereaction was stirred at 80° C. for 4 h

Example 10

NMR Spectrum: ¹H NMR (400 MHz, MeOH-d4) δ 1.77 (6H, d), 1.98-2.10 (2H,m), 2.34 (6H, s), 2.54-2.63 (2H, m), 3.61 (3H, s), 4.41 (2H, t), 5.36(1H, p), 6.88 (1H, dd), 7.87 (1H, dt), 8.08-8.21 (2H, m), 8.53 (1H, s),8.83 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=438.

Example 11

NMR Spectrum: ¹H NMR (400 MHz, MeOH-d4) δ 1.74 (6H, d), 2.04 (2H, ddt),2.34 (6H, s), 2.54-2.63 (2H, m), 3.60 (3H, s), 4.42 (2H, t), 5.30 (1H,p), 6.88 (1H, dd), 7.84 (1H, d), 8.03 (1H, ddd), 8.42 (1H, d), 8.85 (1H,s). Mass Spectrum: m/z (ES+)[M+H]+=456.

Example 12

NMR Spectrum: ¹H NMR (300 MHz, MeOH-d4) δ 1.76 (6H, d), 2.12-2.30 (4H,m), 2.31-2.35 (2H, m), 2.38-3.47 (6H, m), 3.62 (3H, s), 4.50 (2H, t),5.32-5.41 (1H, m), 6.92-6.95 (1H, m), 7.89 (1H, d), 8.15-8.20 (2H, m),8.41 (1H, s), 8.85 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=464.

Example 13

NMR Spectrum: ¹H NMR (400 MHz, MeOH-d4) δ 1.74 (6H, d), 2.08-2.20 (4H,m), 2.24-2.36 (2H, m), 3.39-3.48 (6H, m), 3.61 (3H, s), 4.51 (2H, t),5.30 (1H, t), 6.93 (1H, d), 7.86 (1H, d), 8.08 (1H, t), 8.42 (1H, d),8.87 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=482.

Example 14

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.39 (2H, d), 1.51 (5H, p),1.60 (6H, d), 1.93 (2H, q), 2.43 (6H, d), 3.49 (3H, s), 4.32 (2H, t),5.24 (1H, q), 6.96 (1H, dd), 7.92 (1H, d), 8.07-8.22 (2H, m), 8.38 (1H,d), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=496.

Example 15

NMR Spectrum: ¹H NMR (400 MHz, MeOH-d4) δ 1.64 (6H, d), 1.73 (2H, t),1.96 (2H, p), 2.46-2.51 (2H, t), 3.12 (4H, t), 3.50 (3H, s), 4.28 (2H,t), 5.28 (1H, q), 6.94 (1H, dd), 7.76-7.86 (1H, m), 8.08-8.29 (2H, m),8.43 (1H, s), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=450

Example 16

NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 1.60 (6H, d), 1.70-1.81 (2H,m), 1.96-2.04 (2H, m), 2.55 (2H, s), 3.19 (4H, dt), 3.49 (3H, s), 4.30(2H, t), 5.22 (1H, q), 6.95 (1H, dd), 7.92 (1H, d), 8.08-8.17 (1H, m),8.38 (1H, d), 8.93 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=468.

Intermediate G1:3-[[6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]oxy]-N,N-dimethyl-propan-1-amine

A solution of n-butyllithium (0.693 g, 10.83 mmol) in n-hexane (4.33 mL)was added to a stirred mixture of3-(5-bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine (2 g,7.22 mmol) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.014 g, 10.83 mmol) in THF (20 mL) at −78° C. over a period of 20minutes under an inert atmosphere. The resulting mixture was allowed towarm to ambient temperature and stirred for 2 h. The reaction mixturewas quenched with sat. NaHCO₃ solution and concentrated in vacuo. Thecrude product was purified by FCC, elution gradient 0 to 10% MeOH inDCM, to afford the desired material (2.50 g, 107%). Mass Spectrum: m/z(ES+)[M+H]+=325.

Intermediate G2:3-(5-Bromo-6-fluoropyridin-2-yl)oxy-N,N-dimethylpropan-1-amine

(E)-Diisopropyl diazene-1,2-dicarboxylate (15.80 g, 78.13 mmol) wasadded dropwise to 3-(dimethylamino)propan-1-ol (8.06 g, 78.13 mmol),5-bromo-6-fluoropyridin-2-ol (10 g, 52.09 mmol) and triphenylphosphine(20.49 g, 78.13 mmol) in DCM (150 mL) cooled to 0-5° C. under an inertatmosphere. The resulting solution was stirred at ambient temperaturefor 16 h then the solvent removed under reduced pressure. The residuewas diluted with EtOAc (50 mL) and the solid removed by filtration anddiscarded. The filtrate was acidified with hydrogen chloride in dioxane.The solid was collected by filtration then dissolved in a sat. aqueoussolution of Na₂CO₃ (200 mL) and extracted with EtOAc (3×100 mL). Thecombined organic layers were washed with water, brine, dried over Na₂SO₄and concentrated in vacuo to afford the desired material (9.00 g,62.3%). NMR Spectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.89-1.98 (2H, m), 2.26(6H, s), 2.34 (2H, t), 4.30 (2H, t), 6.53 (1H, d), 7.74 (1H, t). MassSpectrum: m/z (ES+)[M+H]+=277.

Intermediate G3: 5-Bromo-6-fluoropyridin-2-ol

A solution of sodium nitrite (21.67 g, 314.13 mmol) in water (150 mL)was added dropwise to a stirred mixture of5-bromo-6-fluoropyridin-2-amine (50 g, 261.78 mmol) and sulphuric acid(1.2 mL, 22.51 mmol) in water (750 mL) at 0-5° C. The resultingsuspension was stirred for 48 h at ambient temperature then theprecipitate collected by filtration, washed with water (200 mL) anddried under vacuum to afford the desired material (40.0 g, 80%) as apale yellow solid, which was used without further purification. NMRSpectrum: ¹H NMR (300 MHz, DMSO-d6) δ 6.55 (1H, d), 8.00 (1H, t), 11.71(1H, bs). Mass Spectrum: m/z (ES+)[M+H]+=192.

Intermediate G4: 5-Bromo-6-fluoropyridin-2-amine

NBS (50.0 g, 280.99 mmol) was added slowly to 6-fluoropyridin-2-amine(30 g, 267.61 mmol) in MeCN (300 mL) cooled to 10-20° C. over a periodof 30 minutes. The resulting solution was stirred at ambient temperaturefor 60 minutes then the solvent removed under reduced pressure. Theresidue was diluted with water, the precipitate collected by filtration,washed with water (200 mL) and dried under vacuum to afford the desiredmaterial (50.0 g, 98%) as a white solid, which was used without furtherpurification. NMR Spectrum: ¹H NMR (300 MHz, DMSO-d6) δ 6.29 (1H, d),6.57 (2H, bs), 7.65 (1H, t). Mass Spectrum: m/z (ES+)[M+H]+=191.

Intermediate H1:2-Fluoro-6-[3-(1-piperidyl)propoxy]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

PdCl₂(dppf) (0,692 g, 0.95 mmol) was added to3-bromo-2-fluoro-6-(3-(piperidin-1-yl)propoxy)pyridine (3 g, 9.46 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.60 g,14.19 mmol) and potassium acetate (1,856 g, 18.92 mmol) in 1,4-dioxane(60 mL) at ambient temperature under an inert atmosphere. The resultingmixture was stirred at 80° C. for 16 h then cooled and the solventremoved under reduced pressure. The crude product was purified by flashsilica chromatography, elution gradient 0 to 100% EtOAc in petroleumether, to afford the desired material as a red liquid (0.90 g, 26%)which was used without further purification. Mass Spectrum: m/z(ES+)[M+H]+=365. The following boronic ester intermediates were preparedin an analogous fashion from the appropriate bromides.

Intermediate Structure Name I1*

6-[3-(azetidin-1-yl)propoxy]-2-fluoro- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine J1**

2-fluoro-6-(3-pyrrolidin-1-ylpropoxy)- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine *The material was used without purification**The reaction was stirred at 100° C. for 16 h and the material usedwithout purification.

Intermediate I1

Mass Spectrum: m/z (ES+)[M+H]+=337.

Intermediate J1

Mass Spectrum: m/z (ES+)[M+H]+=351.

Intermediate H2: 3-Bromo-2-fluoro-6-[3-(1-piperidyl)propoxy]pyridine

(E)-Di-tert-butyl diazene-1,2-dicarboxylate (7.20 g, 31.25 mmol) wasadded to 3-(piperidin-1-yl)propan-1-ol (4.48 g, 31.25 mmol),triphenylphosphine (8.20 g, 31.25 mmol) and 5-bromo6-fluoropyridin-2-ol(4.0 g, 20.83 mmol) in DCM (50 mL). The resulting mixture was stirred atambient temperature for 18 h then the solvent removed under reducedpressure. The residue was triturated with EtOAc (100 mL) and filtered toremove solid. To the filtrate was added 20 mL HCl (gas) solution indioxane. The solid was collected by filtration. The solid was dissolvedin water (100 mL), basified with a saturated aqueous solution of Na₂CO₃and extracted with EtOAc (200 mL). The organic layer was separated andwashed with saturated brine (50 mL), dried over Na₂SO₄, filtered andevaporated to afford the desired material as a yellow oil (1.50 g,22.70%) which was used without further purification. NMR Spectrum: ¹HNMR (300 MHz, DMSO-d6) δ 1.46-1.51 (6H, m), 1.82-1.89 (2H, m), 2.30-2.51(6H, m), 4.21 (2H, t), 6.74 (1H, d), 8.07 (1H, t). Mass Spectrum: m/z(ES+)[M+H]+=317.

The following bromides were made in an analogous fashion from5-bromo-6-fluoropyridin-2-ol and the appropriate alcohol.

Intermediate Structure Name I2*

6-[3-(azetidin-1-yl)propoxy]-3-bromo-2- fluoro-pyridine J2**

3-bromo-2-fluoro-6-(3-pyrrolidin-1- ylpropoxy)pyridine

Intermediate I2

NMR Spectrum: ¹H NMR (300 MHz, CDCl₃) δ 1.63-1.92 (2H, m), 2.08 (2H, p),2.53 (2H, t), 3.20 (4H, t), 4.27 (2H, t), 6.53 (1H, dd), 7.61-7.81 (1H,m); Mass Spectrum: m/z (ES+)[M+H]+=291

Intermediate J2

Mass Spectrum: m/z (ES+)[M+H]+=303.

Example 178-[6-[3-(Dimethylamino)propoxy]-3-pyridyl]-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (149 mg, 0.19 mmol) was addedtoN,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amine(680 mg, 2.22 mmol),8-bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one (600 mg,1.85 mmol) and Cs₂CO₃ (1508 mg, 4.63 mmol) in 1,4-dioxane (5 mL) andwater (0.5 mL). The to resulting mixture was stirred at 80° C. for 5 h.The crude product was purified by flash silica chromatography, elutiongradient 10 to 20% MeOH in DCM, the pure fractions combined andevaporated to dryness. The product was further purified by flashC18-flash chromatography, elution gradient 5 to 40% MeCN in water, toafford the desired material as a yellow solid (260 mg, 33.2%). NMRSpectrum: ¹H NMR (300 MHz, CDCl₃) δ 0.72 (6H, d), 2.00-2.15 (2H, m),2.37 (6H, s), 2.61-2.66 (2H, m), 4.42 (2H, t), 5.27-5.31 (1H, m), 6.94(1H, d), 7.79 (1H, d), 8.02 (1H, d), 8.32 (1H, d), 8.43 (1H, s), 8.65(1H, s). Mass Spectrum: m/z (ES+)[M+H]+=424.

The following compound was prepared in an analogous fashion from8-bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one and2-[3-(1-piperidyl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.

Example Structure Name 18

7-Fluoro-1-isopropyl-8-[6-[3-(1- piperidyl)propoxy]-3-pyridyl]-3H-imidazo[4,5-c]quinolin-2-one

The preparation of8-bromo-7-fluoro-1-isopropyl-3H-imidazo[4,5-c]quinolin-2-one,N,N-dimethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxypropan-1-amineand2-[3-(1-piperidyl)propoxy]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridinehave been described previously.

Metabolite A

7-Fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-oxidopiperidin-1-ium-1-yl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one

The pH of a solution of potassium phosphate, dibasic (1.74 g, 9.99 mmol)in water (100 mL) was adjusted to pH9 by the addition of 2M hydrochloricacid. A portion of this prepared solution (23 mL) was then added to avessel containing7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one(0.27 g, 0.565 mmol). Propan-2-ol (3.9 mL) was added to the reactionvessel followed by the addition of BVMPO-P1-D08 (0.27 g, 0.000540 mmol),KRED-P1-H10 (54 mg, 0.0011 mmol) and beta-nicotinamide adeninedinucleotide phosphate disodium salt (27 mg, 0.034291 mmol). Thereaction was heated to 32° C. overnight with vigorous stirring (300 rpm)and compressed air blown continuously into the vessel headspace. Furtherpropan-2-ol (3.9 mL) and water (˜10 mL) was added. The reaction mixturewas stirred at 30° C. with stirring (300 rpm) for a further 3 days thendiluted with acetonitrile (40.5 mL), filtered and the filtrateevaporated under reduced pressure until the remaining volume was ˜25 mL.Sodium chloride (˜2 g) was added and the mixture extracted withbutan-1-ol (2×24.3 mL). The extracts were combined, dried over Na₂SO₄,and concentrated to give a brown solid. The crude material was purifiedby silica chromatography, eluting with a mixture of DCM/MeOH/cNH₃(125:10:1), to afford the desired material as an off white solid (0.040g, 14%). NMR Spectrum: ¹HNMR (500 MHz, DMSO-d6) δ 1.2-1.31 (1H, m), 1.44(2H, d), 1.56 (1H, d), 1.63 (6H, d), 2.04-2.17 (2H, m), 2.25-2.33 (2H,m), 2.91 (2H, d), 3.10 (2H, td), 3.19-3.26 (2H, m), 3.49 (3H, s), 4.44(2H, t), 5.27 (1H, p), 6.98 (1H, dd), 7.91 (1H, d), 8.05 (1H, dt), 8.31(1H, d), 8.50 (1H, s), 8.90 (1H, s). Mass Spectrum: m/z (ES+)[M+H]+=494.

Biological Assays

The following assays were used to measure the effects of the compoundsof the present invention: a) ATM cellular potency assay; b) PI3Kcellular potency assay; c) mTOR cellular potency assay; d) ATR cellularpotency assay. During the description of the assays, generally:

-   -   i. The following abbreviations have been used:        4NQO=4-Nitroquinoline N-oxide; Ab=Antibody; BSA=Bovine Serum        Albumin; CO₂=Carbon Dioxide; DMEM=Dulbecco's Modified Eagle        Medium; DMSO=Dimethyl Sulphoxide;        EDTA=Ethylenediaminetetraacetic Acid; EGTA=Ethylene Glycol        Tetraacetic Acid; ELISA=Enzyme-linked Immunosorbent Assay;        EMEM=Eagle's Minimal Essential Medium; FBS=Foetal Bovine Serum;        h=Hour(s); HRP=Horseradish Peroxidase; i.p.=intraperitoneal;        PBS=Phosphate buffered saline; PBST=Phosphate buffered        saline/Tween; TRIS=Tris(Hydroxymethyl)aminomethane; MTS reagent:        [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium,        inner salt, and an electron coupling reagent (phenazine        methosulfate) PMS; s.c.=sub-cutaneously.    -   ii. IC₅₀ values were calculated using a smart fitting model in        Genedata. The IC₅₀ value was the concentration of test compound        that inhibited 50% of biological activity.

Assay a): ATM Cellular Potency Rationale:

Cellular irradiation induces DNA double strand breaks and rapidintermolecular autophosphorylation of serine 1981 that causes dimerdissociation and initiates cellular ATM kinase activity. Most ATMmolecules in the cell are rapidly phosphorylated on this site afterdoses of radiation as low as 0.5 Gy, and binding of a phosphospecificantibody is detectable after the introduction of only a few DNAdouble-strand breaks in the cell.

The rationale of the pATM assay is to identify inhibitors of ATM incells. HT29 cells are incubated with test compounds for 1 hr prior toX-ray-irradiation. 1 h later the cells are fixed and stained for pATM(Ser1981). The fluorescence is read on the arrayscan imaging platform.

Method Details:

HT29 cells (ECACC #85061109) were seeded into 384 well assay plates(Costar #3712) at a density of 3500 cells/well in 40 μl EMEM mediumcontaining 1% L glutamine and 10% FBS and allowed to adhere overnight.The following morning compounds of Formula (I) in 100% DMSO were addedto assay plates by acoustic dispensing. After 1 h incubation at 37° C.and 5% CO₂, plates (up to 6 at a time) were to irradiated using theX-RAD 320 instrument (PXi) with equivalent to ˜600 cGy. Plates werereturned to the incubator for a further 1 h. Then cells were fixed byadding 20 μl of 3.7% formaldehyde in PBS solution and incubating for 20minutes at r.t. before being washed with 50 μl/well PBS, using a BiotekEL405 plate washer. Then 20 μl of 0.1% Triton X100 in PBS was added andincubated for 20 minutes at r.t., to permeabalise cells. Then the plateswere washed once with 50 μl/well PBS, using a Biotek EL405 plate washer.

Phospho-ATM Ser1981 antibody (Millipore # MAB3806) was diluted 10000fold in PBS containing 0.05% polysorbate/Tween and 3% BSA and 20 μl wasadded to each well and incubated over night at r.t. The next morningplates were washed three times with 50 μl/well PBS, using a Biotek EL405plate washer, and then 20 μl of secondary Ab solution, containing 500fold diluted Alexa Fluor® 488 Goat anti-rabbit IgG (Life Technologies,A11001) and 0.002 mg/ml Hoeschst dye (Life technologies # H-3570), inPBS containing 0.05% polysorbate/Tween and 3% BSA, was added. After 1 hincubation at r.t., the plates were washed three times with 50 μl/wellPBS, using a Biotek EL405 plate washer, and plates were sealed and keptin PBS at 4° C. until read. Plates were read using an ArrayScan VTIinstrument, using an XF53 filter with 10× objective. A two laser set upwas used to analyse nuclear staining with Hoeschst (405 nm) andsecondary antibody staining of pSer1981 (488 nm).

Assay b): ATR Cellular Potency Rationale:

ATR is a PI 3-kinase-related kinase which phosphorylates multiplesubstrates on serine or threonine residues in response to DNA damageduring or replication blocks. Chk1, a downstream protein kinase of ATR,plays a key role in DNA damage checkpoint control. Activation of Chk1involves phosphorylation of Ser317 and Ser345 (the latter regarded asthe preferential target for phosphorylation/activation by ATR). This wasa cell based assay to measure inhibition of ATR kinase, by measuring adecrease in phosphorylation of Chk1 (Ser 345) in HT29 cells, followingtreatment with compound of Formula (I) and the UV mimetic 4NQO (Sigma #N8141).

Method Details:

HT29 cells (ECACC #85061109) were seeded into 384 well assay plates(Costar #3712) at a density of 6000 cells/well in 40 μl EMEM mediumcontaining 1% L glutamine and 10% FBS and allowed to adhere overnight.The following morning compound of Formula (I) in 100% DMSO were added toassay plates by acoustic dispensing. After 1 h incubation at 37° C. and5% C02, 40 nl of 3 mM 4NQO in 100% DMSO was added to all wells byacoustic dispensing, except minimum control wells which were leftuntreated with 4NQO to generate a null response control. Plates werereturned to the incubator for a further 1 h. Then cells were fixed byadding 20 μl of 3.7% formaldehyde in PBS solution and incubating for 20mins at r.t. Then 20 μl of 0.1% Triton X100 in PBS was added andincubated for 10 minutes at r.t., to permeabalise cells. Then the plateswere washed once with 50 μl/well PBS, using a Biotek EL405 plate washer.

Phospho-Chk1 Ser 345 antibody (Cell Signalling Technology #2348) wasdiluted 150 fold in PBS containing 0.05% polysorbate/Tween and 15 μl wasadded to each well and incubated over night at r.t. The next morningplates were washed three times with 50 μl/well PBS, using a Biotek EL405plate washer, and then 20 μl of secondary Ab solution, containing 500fold diluted Alexa Fluor 488 Goat anti-rabbit IgG (Molecular Probes #A-11008) and 0.002 mg/ml Hoeschst dye (Molecular Probes # H-3570), inPBST, was added. After 2 h incubation at r.t., the plates were washedthree times with 50 μl/well PBS, using a Biotek EL405 plate washer, andplates were then sealed with black plate seals until read. Plates wereread using an ArrayScan VTI instrument, using an XF53 filter with 10×objective. A two laser set up was used to analyse nuclear staining withHoeschst (405 nm) and secondary antibody staining of pChkl (488 nm).

Assay c): PI3K Cellular Potency Rationale:

This assay was used to measure PI3K-α inhibition in cells. PDK1 wasidentified as the upstream activation loop kinase of protein kinase B(Akt1), which is essential for the activation of PKB. Activation of thelipid kinase phosphoinositide 3 kinase (PI3K) is to critical for theactivation of PKB by PDK1.

Following ligand stimulation of receptor tyrosine kinases, PI3K isactivated, which converts PIP2 to PIP3, which is bound by the PH domainof PDK1 resulting in recruitment of PDK1 to the plasma membrane where itphosphorylates AKT at Thr308 in the activation loop.

The aim of this cell-based mode of action assay is to identify compoundsthat inhibit PDK activity or recruitment of PDK1 to membrane byinhibiting PI3K activity. Phosphorylation of phospho-Akt (T308) inBT474c cells following treatment with compounds for 2 h is a directmeasure of PDK1 and indirect measure of PI3K activity.

Method Details:

BT474 cells (human breast ductal carcinoma, ATCC HTB-20) were seededinto black 384 well plates (Costar, #3712) at a density of 5600cells/well in DMEM containing 10% FBS and 1% glutamine and allowed toadhere overnight.

The following morning compounds in 100% DMSO were added to assay platesby acoustic dispensing. After a 2 h incubation at 37° C. and 5% CO₂, themedium was aspirated and the cells were lysed with a buffer containing25 mM Tris, 3 mM EDTA, 3 mM EGTA, 50 mM sodium fluoride, 2 mM Sodiumorthovanadate, 0.27M sucrose, 10 mM f3-glycerophosphate, 5 mM sodiumpyrophosphate, 0.5% Triton X-100 and complete protease inhibitorcocktail tablets (Roche #04 693 116 001, used 1 tab per 50 ml lysisbuffer).

After 20 minutes, the cell lysates were transferred into ELISA plates(Greiner #781077) which had been pre-coated with an anti total-AKTantibody in PBS buffer and non-specific binding was blocked with 1% BSAin PBS containing 0.05% Tween 20. Plates were incubated over night at 4°C. The next day the plates were washed with PBS buffer containing 0.05%Tween 20 and further incubated with a mouse monoclonal anti-phospho AKTT308 for 2 h. Plates were washed again as above before addition of ahorse anti-mouse-HRP conjugated secondary antibody. Following a 2 hincubation at r.t., plates were washed and QuantaBlu substrate workingsolution (Thermo Scientific #15169, prepared according to provider'sinstructions) was added to each well. The developed fluorescent productwas stopped after 60 minutes by addition of Stop solution to the wells.Plates were read using a Tecan Safire plate reader using 325 nmexcitation and 420 nm emission wavelengths respectively. Except wherespecified, reagents contained in the Path to Scan Phospho AKT (Thr308)sandwich ELISA kit from Cell Signalling (#7144) were used in this ELISAassay.

Assay d): mTOR Cellular Potency

Rationale:

This assay was used to measure mTOR inhibition in cells. The aim of thephospho-AKT cell based mechanism of action assay using the AcumenExplorer is to identify inhibitors of either PI3Kα or mTOR-Rictor(Rapamycin insensitive companion of mTOR). This is measured by anydecrease in the phosphorylation of the Akt protein at Ser473 (AKT liesdownstream of PI3Kα in the signal transduction pathway) in theMDA-MB-468 cells following treatment with compound.

Method Details:

MDA-MB-468 cells (human breast adenocarcinoma # ATCC HTB 132) wereseeded at 1500 cells/well in 40 μl of DMEM containing 10% FBS and 1%glutamine into Greiner 384 well black flat-bottomed plates. Cell plateswere incubated for 18 h in a 37° C. incubator before dosing withcompounds of Formula (I) in 100% DMSO using acoustic dispensing.Compounds were dosed in a 12 point concentration range into a randomisedplate map. Control wells were generated either by dosing of 100% DMSO(max signal) or addition of a reference compound (a PI3K-β inhibitor)that completely eliminated the pAKT signal (min control). Compounds werethen tested by one of two assay protocols A or B:

Protocol A:

Plates were incubated at 37° C. for 2 h; cells were then fixed by theaddition of 10 μl of a 3.7% formaldehyde solution. After 30 minutes theplates were washed with PBS using a Tecan PW384 plate washer. Wells wereblocked and cells permeabilised with the addition of 40 μl of PBScontaining 0.5% Tween20 and 1% Marvel™ (dried milk powder) and incubatedfor 60 minutes at r.t. The plates were washed with PBS containing 0.5%(v/v) Tween20 and 20 μl rabbit anti-phospho AKT Ser473 (Cell SignallingTechnologies, #3787) in same PBS-Tween+1% Marvel™ was added andincubated overnight at 4° C.

Plates were washed 3 times with PBS+0.05% Tween 20 using a Tecan PW384.20 μl of secondary antibody Alexa Fluor 488 anti-Rabbit (MolecularProbes, # A11008) diluted in PBS+0.05% Tween20 containing 1% Marvel™ wasadded to each well and incubated for 1 h at r.t. Plates were washedthree times as before then 20 μl PBS added to each well and platessealed with a black plate sealer.

The plates were read on an Acumen plate reader as soon as possible,measuring green fluorescence after excitation with 488 nm laser. Usingthis system ICso values were generated and quality of plates wasdetermined by control wells. Reference compounds were run each time tomonitor assay performance.

Protocol B:

The cell plates were then incubated for 2 h at 37° C. before being fixedby the addition of 20 μl 3.7% formaldehyde in PBS/A (1.2% finalconcentration), followed by a 30 minute room temperature incubation, andthen a 2× wash with 150 μl PBS/A using a BioTek ELx406 platewasher.Cells were permeabilised and blocked with 20 μl of assay buffer (0.1%Triton X-100 in PBS/A+1% BSA) for 1 h at room temperature, and thenwashed 1× with 50 μl PBS/A. Primary phospho-AKT (Ser473) D9E XP® rabbitmonoclonal antibody (#4060, Cell Signaling Technology) was diluted 1:200in assay buffer, 20 μl added per well, and plates were incubated at 4°C. overnight. Cell plates were washed 3× with 200 μl PBS/T, then 20 μl1:750 dilution in assay buffer of Alexa Fluor® 488 goat anti-rabbit IgGsecondary antibody (# A11008, Molecular Probes, Life Technologies), witha 1:5000 dilution of Hoechst 33342, was added per well. Following a 1 hincubation at room temperature, plates were washed 3× with 200 μl PBS/T,and 40 μl PBS w/o Ca, Mg and Na Bicarb (Gibco #14190-094) was added perwell.

Stained cell plates were covered with black seals, and then read on theCell Insight imaging platform (Thermo Scientific), with a 10× objective.The primary channel (Hoechst blue fluorescence 405 nM, BGRFR_386_23) wasused to Autofocus and to count number of events (this providedinformation about cytotoxicity of the compounds tested). The secondarychannel (Green 488 nM, BGRFR_485_20) measured pAKT staining. Data wasanalysed and ICsos were calculated using Genedata Screener® software.

Table 2 shows the results of testing the Examples in tests a) b) c) andd). Results may be the geometric mean of several tests.

TABLE 2 Potency Data for Examples 1-18 in Assays a)-d) Assay c) Assay d)Assay a) ATM Assay b) ATR PI3Kα Cell mTOR Cell Example Cell IC₅₀ (μM)Cell IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM)  1   0.000879 >30   13.4 >30*  2  0.000787 >30 >12 >30*  3   0.000824 >30   11.4 >20^(§)  4  0.00159 >30    4.52 >30^(§)  5   0.000253   17.9    1.24    6.76*  6  0.000398 >20.7    0.184  >3.12^(§)  7   0.000256 >30    0.222    3.19* 8   0.000698    0.661    0.405*  9 <0.000453 >30    5.75  >5.19^(§) 10  0.000686 >30    6.18    3.49* 11   0.00228 >30   23.6§ 12  0.000799 >30    2.89 >10* 13   0.00132 >30   22.9 >30* 14  0.00351 >30 >30 >30* 15   0.00214 >30  >0.300* 16   0.00229 >30   9.08 >29.9^(§) 17   0.00461 >30 >10* 18   0.00314 >30 >30 >30^(§)^(§)Result obtained using assay d) Protocol A *Result obtained usingassay d) Protocol B

Table 3 shows comparative data for certain Compounds of CN102399218A and5 CN102372711A in tests a) b) c) and d). Results may be the geometricmean of several tests.

TABLE 3 Potency Data for Certain Compounds of CN102399218A andCN102372711A in Assays a)-d) Assay a) Assay b) Assay c) Assay d)Reference ATM Cell ATR Cell PI3Ka Cell mTOR Cell Compound IC₅₀ (μM) IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) CN102372711A 0.125 0.281 0.188 0.237 Compound 1CN102372711A 0.0112 0.0686 0.102 0.0729 Compound 4 CN102372711A 0.02650.0644 0.153 0.113 Compound 5 CN102399218A 1.76 0.419 4.67 2.31 Compound60 CN102399218A 3.46 1.48 1.73 0.177 Compound 61 CN102399218A 0.1350.0553 0.149 0.0155 Compound 62 CN102399218A 0.216 0.162 0.247 0.287Compound 64 CN102399218A 0.494 0.0129 0.0804 0.0414 Compound 94CN102399218A 0.0741 0.0686 0.0131 0.0469 Compound 114

Table 4 shows the results of testing Metabolite A in tests a) b) c) andd). Results may be the geometric mean of several tests.

TABLE 4 Potency Data for Metabolite A in Assays a)-d) Assay a) Assay b)Assay c) Assay d) ATM Cell ATR Cell PI3Kα Cell mTOR Cell Compound IC₅₀(μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) Metabolite A 0.035 9.41 27.8 >30**Result obtained using assay d) Protocol B

1-15. (canceled)
 16. A crystalline form (Form A) of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one.17. The crystalline form (Form A) of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,according to claim 16, which has an X-ray powder diffraction patternwith at least two specific peaks at about 2-theta=3.7 and 14.8° (plus orminus 0.2° 2-theta).
 18. The crystalline form (Form A) of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,according to claim 16, which has an X-ray powder diffraction patternwith specific peaks at 2-theta=3.7, 11.3, 13.1, 14.8, 18.0, 18.4, 19.4,21.0, 22.3 and 23.2° (plus or minus 0.2° 2-theta).
 19. The crystallineform (Form A) of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,according to claim 16, which has a differential scanning calorimetrythermogram having an endotherm peak at about 144.2° C. (plus or minus 5°C.) with an onset of about 141.5° C. (plus or minus 5° C.).
 20. A methodfor treating Huntington's disease in a warm-blooded animal in need ofsuch treatment, which comprises administering to said warm-bloodedanimal a therapeutically effective amount of7-fluoro-1-isopropyl-3-methyl-8-[6-[3-(1-piperidyl)propoxy]-3-pyridyl]imidazo[4,5-c]quinolin-2-one,or a pharmaceutically acceptable salt thereof.